Transition metal complexes for enantioselective catalysis of carbon-carbon, carbon-heteroatom, and carbon-hydrogen bond forming reactions

ABSTRACT

In some embodiments, the present disclosure pertains to a compound, comprising a transition metal complex having the formula Φ-[M (x,y)-L 1  (w,v)-L 2  (t,u)-L 3 ] p+ An −   m Z −   p-m . In an embodiment of the present disclosure Φ may be Λ. In another embodiment Φ may be Λ. In some embodiments of the present disclosure, M is a transition metal. In a related embodiment, p is an integer corresponding to the oxidation state of M. In some embodiments of the present disclosure, each of x, y, w, v, t, and u independently comprise R. In other embodiments, each of x, y, w, v, t, and u independently comprise S. In an embodiment of the present disclosure, each of L 1 , L 2 , and L 3  independently is a ligand comprising a substituted diamine. In some embodiments, An −  comprises a lipophilic anion, where m is from 1 to 3, and where Z −  comprises an optional second anion.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 14/417,655, filed on Jul. 29, 2013. This application claimspriority to U.S. Provisional Application No. 61/676,683, filed Jul. 27,2012. The entirety of the aforementioned applications is incorporatedherein by reference.

FIELD

This invention relates to transition metal/substituted organo di-amineligand complexes and their function as catalysts, particularly forcarbon-carbon, carbon-heteroatom, and carbon-hydrogen bond formingreactions.

BACKGROUND

Enantioselective catalysts are desirable for producing high value addedenantiopure chemicals. Examples of applications of enantiopure chemicalsare as pharmaceutical chemicals and as agricultural chemicals.Production of pharmaceutical chemicals or that of agricultural chemicalstends to involve carbon-carbon, carbon-heteroatom, and/orcarbon-hydrogen bond forming reactions. Enantiopure chemicals may bealternately described as optically active, or as right or left rotationforms, or as chiral. Enantiopure chemicals possess the characteristicthat they have a 3 dimensional handedness and are substantially pure. Inaddition, enantiopure chemicals can be at least one of the other of twoforms that are not mirror images of each other.

The use of existing transition metal complexes as catalysts, formediating carbon-carbon, carbon-heteroatom, and carbon-hydrogen bondforming reaction, is limited for commercial applications. The limitedcommercial use is attributed to the existing transition metal complexesbeing substitution labile, having poor solubility in organic solvents,or further having low enantioselectivity. Therefore, there remains aneed for substitution inert transition metal complexes with activity asenantioselective catalysts for carbon-carbon, carbon-heteroatom, andcarbon-hydrogen bond forming reactions that are suitable forcommercial/industrial applications.

SUMMARY

In some embodiments, the present disclosure pertains to a compound,comprising a transition metal complex having the formula Φ-[M (x,y)-L₁(w,v)-L₂ (t,u)-L₃]^(p+)An⁻ _(m)Z⁻ _(p-m). In an embodiment of thepresent disclosure Φ may be Λ. In another embodiment Φ may be Λ. In someembodiments of the present disclosure, M is a transition metal. In someembodiments, p is an integer corresponding to the oxidation state of M.In some embodiments of the present disclosure, each of x, y, w, v, t,and u independently comprise R. In other embodiments, each of x, y, w,v, t, and u independently comprise S. In some embodiments of the presentdisclosure, each of L₁, L₂, and L₃ independently is a ligand comprisinga substituted diamine. In some embodiments An⁻ comprises a lipophilicanion, where m is from 1 to 3, and where Z⁻ comprises an optional secondanion.

In some embodiments, the present disclosure relates to a compoundcomprising a transition metal complex having the formula Φ-[M((x,y)-L₁)_(3-b-c) ((w,v)-L₂)_(b)((t,u)-L₃)_(c)]^(p+)An⁻ _(m)Z⁻ _(p-m).In some embodiments of the present disclosure, Φ is Λ. In someembodiments of the present disclosure, Φ is Λ. In some embodiments ofthe present disclosure, M is a transition metal. In some embodiments, pis an integer corresponding to the oxidation state of M. In someembodiments, each of x, y, w, v, t, and u independently comprises R. Inother embodiments, each of x, y, w, v, t, and u independently comprisesS. In some embodiments, each of L₁, L₂ and L₃ independently is a ligandcomprising ethylene diamine. In some embodiments, L₃ is a ligandcomprising a pendant Lewis base derivative of ethylene diamine. In someembodiments, c is from 1 to 3. In some embodiments, b is from 0 to 2. Insome embodiments of the present disclosure, An⁻ comprises a lipophilicanion, where m is from 1 to 3, and where Z⁻ comprises a second anion.

In some embodiments, the present disclosure relates to a compoundcomprising a transition metal complex having the formula Φ-[M (x,y)-L₁(w,v)-L₂XY]^((p+a)+)An⁻ _(m)Z⁻ _(p-m). In some embodiments, Φ is Λ. Insome embodiments, Φ is Λ. In some embodiments of the present disclosure,M is a transition metal. In some embodiments, p is an integercorresponding to the oxidation state of M. In some embodiments of thepresent disclosure, each of x, y, w, and v is independently R. In otherembodiments, each of x, y, w, and v is independently S. In someembodiments of the present disclosure, each of L₁ and L₂ comprises achelating ligand comprising at least two nitrogens. In some embodiments,each of L₁ and L₂ independently comprises a chelating ligand comprisingat least two metal coordinating atoms. In some embodiments of thepresent disclosure, Y comprises a mono-coordinated diamine ligand. Insome embodiments of the present disclosure, X comprises one out of asecond mono-coordinated diamine ligand and a nucleophilic ligand. Insome embodiments, “a” is the total charge of the mono-coordinatedligand(s). In some embodiments of the present disclosure, An⁻ comprisesa lipophilic anion, where m is from 1 to p, and where Z⁻ comprises asecond optional anion.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the two chiral configurations that center at the metal, Λand Δ, illustrated with 3(S,S)-diphenylethylenediamine (DPEN) ligandsand cobalt (Co) metal, Λ-[Co((S,S)-dpen)3]³⁺ and Δ-[Co((S,S)-dpen)3]³⁺respectively;

FIG. 2 represents three possible stereoisomeric arrangements fordiphenylethylenediamine (DPEN): (S,S)-DPEN, (R,R)-DPEN, and (S,R)-DPEN;

FIG. 3 shows the two configurations at the metal center, Λ and Δ, foreach possible combination of the 3 chelating ligands;

FIG. 4 illustrates a procedure to prepare derivatives of DPEN ligand;

FIGS. 5A-5B illustrate a general procedure to prepare DPEN ligandderivatives, where FIG. 5A illustrates forming an intermediate cobaltcomplex with conventional anions forming a precursor cobalt salt, wherethe anion of the intermediate cobalt complex is the same as the anion ofthe precursor cobalt, and FIG. 5B illustrates forming a cobalt complexsoluble in organic solvent by replacing at least one conventional anionswith a lipophilic anion;

FIGS. 6A-6B show an illustrative carbon-carbon bond forming reaction toform enantiomer catalyzed by the Type 1 transition metal complexesdisclosed herein, where FIG. 6A illustrates use of the catalyst obtainedby procedure 1 described herein and FIG. 6B illustrates use of thecatalyst obtained by procedure 1b described herein;

FIG. 7 shows an illustrative carbon-heteroatom bond forming reactioncatalyzed by the catalysts obtained by procedure 2 described herein;

FIG. 8 shows various Type 2 transition metals (cobalt amine) complexeswith cationic backbone prepared using a substituted chiral ethylenediamine ligands having a pendant Lewis base in its side arm. X is theamount of the substituted chiral ethylene diamine ligands having apendant Lewis base in its side arm;

FIG. 9 shows a series of substituted chiral ethylene diamine ligands,having pendant Lewis base in its side arm.

FIG. 10 shows ligands with possible (S) configuration and (R)configuration at the chiral center;

FIG. 11 shows variation, in length of the tether and wide variety ofbasic functional moieties incorporated into the ligands, to tune thebasicity of the Lewis base;

FIG. 12 shows that the two stereoisomers (or diastereomers) that thecobalt complex (X=1) can exist in, when the ligand has (S) configurationin the chiral center, n=3 and R₁=R₂=Me;

FIG. 13 shows Λ and Δ stereoisomers (or diastereomers) of the cobaltcomplex with the ligand which has (R) configuration in the chiralcenter;

FIG. 14 shows the six stereoisomers (or diastereomers) of the cobaltcomplex (X=2), when the ligand has (S) configuration in the chiralcenter, n=3 and R₁=R₂=Me. The three Λ isomers are shown on the left andthree Δ isomers are shown in the right;

FIG. 15 shows the four different stereoisomers (or diastereomers)possible when cobalt is attached to three ligands (X=3) with (S)configuration in the chiral center, n=3 and R₁=R₂=Me;

FIG. 16 shows synthesis of the salt of the ligand(S)—N⁵,N⁵-dimethylpentane-1,2,5-triamine (n=3);

FIG. 17 shows the hydrochloric acid salt of the(S)-5-(pyrrolidin-1-yl)pentane-1,2-diamine;

FIG. 18 shows the synthesis of the hydrochloric acid salt of(S)—N⁴,N⁴-dimethylbutane-1,2,4-triamine (n=2);

FIG. 19 shows the structure of the orange solid[Co(en)₂(S)-enCH₂CH₂CH₂NMe2H]⁴⁺4Cl⁻;

FIG. 20 shows the structure of the compound in the first fractionobtained from the Dowex column during the synthesis and purification ofcobalt complexes (Fr-1 [Co(en)₂(S)-enCH₂CH₂CH₂NMe2H]⁴⁺4Cl⁻.3.5H₂O);

FIG. 21 shows the structure of[Co(en)₂(S)-enCH₂CH₂CH₂NMe2H]⁴⁺4Cl⁻.8H₂O);

FIG. 22 shows the structure of [Co(en)₂(S)-en CH₂CH₂CH₂NMe₂]³+3BAr_(f) ⁻.6.5H₂O;

FIG. 23 shows the structure [Co(en)₂(S)-en CH₂CH₂CH₂NMe₂]³⁺3 BAr_(f) ⁻.15H₂O;

FIG. 24 shows the structure of [Co(en)₂(S)-enCH₂CH₂NMe₂H]⁴⁺⁴Cl⁻;

FIG. 25 shows the structure of [Co(en)₂(S)-enCH₂CH₂NMe₂H]⁴⁺4Cl⁻.4H₂O;

FIG. 26 shows the structure of [Co(en)₂(S)-enCH₂CH₂NMe₂H]⁴⁺4Cl⁻.xH₂0;

FIG. 27 shows the structure of [Co(en)₂(S)-en CH₂CH₂NMe₂]³⁺3BArf-.12H₂O;

FIG. 28 shows the structure of [Co((S)-enCH₂CH₂CH₂NMe₂H)₃]⁶⁺6Cl⁻;

FIG. 29 shows the results of the catalyzed Michael addition oftrans-β-nitrostyrene and diethyl malonate ranged from 76-85% R usingFr-1 [Co(en)₂(S)-en CH₂CH₂CH₂NMe₂]³⁺3BAr_(f) ⁻ .6.5H₂O;

FIG. 30 depicts the Type 3 transition metal complex in cis configurationwhich is considered a “chiral-at-metal metal center” or “stereogenicmetal center”. The minimum requirement for an octahedral (6 bindingsites) metal complex is to have 2 chelating ligands in the cisconfiguration (chelating means one ligand binds at two different sites).The metal is a chiral center in the cis configuration whenever X=Y orwhen X≠Y;

FIG. 31 depicts the Type 3 transition metal complex with transconfiguration which is never considered a “chiral-at-metal” center;

FIG. 32 illustrates an example of possible arrangements of ligandscoordinated to a metal in a Type 3 transition metal complex;

FIGS. 33-34 show that the chelating ligand can take several shapes in aType 3 transition metal complex. Nitrogen is illustrative of a metalcoordinating element;

FIGS. 35-36 show examples of X and Y ligands of Type 3 transition metalcomplexes. At least one of X and Y is a diamine. The diamine can beachiral (FIG. 35) or chiral (FIG. 36);

FIG. 37 shows a typical Type 3 transition metal complex;

FIG. 38 shows a synthesis procedure for cobalt complexes having 1°/3°ligand (L);

FIG. 39 shows the structure of cis-[Co(en)₂(NH₃)Cl]Cl₂ prepared by theprocedure described in FIG. 38;

FIG. 40 shows the structure of cis-[Co(en)2(NH₃)NO₃]Cl₂ prepared by theprocedure described in FIG. 38; and

FIG. 41 shows the structure ofcis-[Co(en)₂(NH₃){(NH₂(CH₂)₂(NMe₂H+Cl—)}]Cl₂ prepared by the proceduredescribed in FIG. 38.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory only,and are not restrictive of the invention, as claimed. In thisapplication, the use of the singular includes the plural, the word “a”or “an” means “at least one”, and the use of “or” means “and/or”, unlessspecifically stated otherwise. Furthermore, the use of the term“including”, as well as other forms, such as “includes” and “included”,is not limiting. Also, terms such as “element” or “component” encompassboth elements or components comprising one unit and elements orcomponents that comprise more than one unit unless specifically statedotherwise.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in this application,including, but not limited to, patents, patent applications, articles,books, and treatises, are hereby expressly incorporated herein byreference in their entirety for any purpose. In the event that one ormore of the incorporated literature and similar materials defines a termin a manner that contradicts the definition of that term in thisapplication, this application controls.

Described in U.S. Pat. No. 4,598,091 are(1,2)-diphenyl-ethylenediamine-platinum (II) complex compounds withantitumor activity. The compounds described have one(1,2)-diphenyl-ethylenediamine portion that may be optically active andtwo of an X ligand that is a physiologically compatible anion. ThePt(II) compounds described tend to be substitution labile. Substitutionlabile ligands tend to go on and off a metal center easily.

Described in U.S. Pat. No. 6,410,749 is a process for the preparation ofoptically active amino alcohols from corresponding α-aminocarbonylcompounds in the presence of an optically active transition metalcomplex. The transition metal complexes described tend to be soluble inorganic solvents and to be substitution labile. Substitution lability ina catalyst tends to open up a binding site available for reactions.

Werner complexes were introduced by Werner in 1911. Werner salts of thechiral tris(ethylenediamine)-substituted octahedral cation [Co(en)₃]³⁺and related species have played important historical roles in thedevelopment of inorganic chemistry and stereochemistry. However, theknown salts of [Co(en)₃]³⁺′ such as [Co(en)₃]³⁺(Cl⁻)₃, have beengenerally regarded as undesirable for catalysis because a) they aresoluble only in water, whereas most industrial processes occur inorganic solvents; and b) they are substitution inert, in that thecomplexes contained ligands that did not go on and off the metal centereasily, to open up a binding site for reactions.

Described in Chem. Euro. J. 2008, 14, 5397-5400, by C. Ganzmann and J.Gladysz, is phase transfer of enantiopure Werner cations into organicsolvents: an overlooked family of chiral hydrogen bond donors forenantioselective catalysis. This reference described Δ-[Co(en)3]³⁺(Cl⁻)₂(BAr_(f) ⁻ )₃.14H₂O where BAr_(f) ⁻ istetrakis[(3,5-trifluromethyl)phenyl]borate. This complex was reported tobe soluble in CH₂Cl₂, acetone, ethyl acetate, THF, DMSO, and alcohols.The NH bonds of the complex were thought to be catalytic sites. However,the reported enantioselectivity was 33%, which tends to be insufficientfor commercial applications. The work is further described in a master'sthesis of Carola Ganzmann, reporting similarly low enantioselectivity. Aneed in the art exists for substitution inert metal complexes that canfunction as enantioselective catalysts for producing high value addedenantiopure chemicals for commercial use.

The present disclosure relates to transition metal/substituted organodi-amine ligand complexes and their function as catalysts, particularlyfor carbon-carbon, carbon-heteroatom, and carbon-hydrogen bond formingreactions. More particularly, the present disclosure, in someembodiments relates to such complexes incorporating cobalt (Co), iron(Fe), nickel (Ni), chromium (Cr), manganese (Mn), molybdenum (Mo),tungsten (W), rhenium (Re), ruthenium (Ru), technetium (Tc), osmium(Os), rhodium (Rh), iridium (Jr), platinum (Pt), or palladium (Pd). Insome embodiments, the present disclosure pertains to such complexesincorporating cobalt, iron, or nickel. Specifically, in someembodiments, the present disclosure relates to such complexesincorporating cobalt.

The transition metal complexes disclosed herein present a new class ofcomplexes soluble in organic solvents and suitable as catalysts forenantioselective organic synthesis. The present inventors havediscovered identities and arrangements of ligands that providesufficient enantioselectivity to the transition metal complexes forcommercial application as catalysts for the manufacture of enantiopurechemicals. As used herein, enantioselectivity may be expressed asenantiomeric excess. According to some embodiments, the transition metalcomplex has activity in enantioselective hydrogen bond mediatingcatalysis. According to some embodiments, the hydrogen bond mediatingcatalysis is suitable for carbon-carbon bond forming reactions. In someembodiments, the hydrogen bond mediating catalysis is suitable forcarbon-heteroatom bond forming reactions. Alternatively or incombination, according to some embodiments, the hydrogen bond mediatingcatalysis is suitable for carbon-hydrogen bond forming reactions. Thepresent metal complexes have the advantage of at least 60%entantioselectivity. For example, enatioselectivities of at least 75%have been achieved. More particularly, enantioselectivities of at least85% have been achieved. Still more particularly, enantioselectivities ofat least 94% have been achieved. The transition metal complexesdisclosed herein further have the advantage of producing high yields.For example, conversions of at least 95% have been achieved. Moreparticularly, conversions of at least 97% have been achieved. Still moreparticularly, conversions of at least 99% have been achieved.

According to some embodiments, transition metal complexes of type 1 arerepresented by the formula Φ-[M (x,y)-L₁ (w,v)-L₂ (t,u)-L₃]^(p+)An⁻_(m)Z⁻ _(p-m), where Φ is Λ or Δ, where M is a transition metal, where pcorresponds to the oxidation state of M, where each of x, y, w, v, t,and u is independently R or S, where each of L₁, L₂, and, L₃independently represents a ligand that is a substituted diamine, whereAn⁻ represents a lipophilic anion, m is from 1 to 3, and where Z⁻represents a conventional anion. Suitable substituted diamines include,but are not limited to, diphenylethylenediamine, derivatives ofdiphenylethylenediamine, and cyclohexanediamine.

According to some embodiments, transition metal complexes of type 2 arerepresented by the formula Φ-[M((x,y)-L₁)_(3-b-c)((w,v)-L₂)_(b)((t,u)-L₃)_(c)]^(p+)An⁻ _(m)Z⁻ _(p-m),where Φ is Λ or Δ, M is a transition metal, p corresponds to theoxidation state of M, where each of x, y, w, v, t, and u isindependently R or S, where each of L₁ and L₂ independently represents aligand that is ethylene diamine (also herein termed “EN” or alternatelydiaminoethane), where L₃ represents a ligand that comprises a pendantLewis base derivative of EN, where c is from 1 to 3, where b is from 0to 2, where An⁻ represents a lipophilic anion, where m is from 1 to 3,and where Z⁻ represents a conventional anion. Suitable ligandscomprising a pendant Lewis base derivative of EN include, but are notlimited to, EN(CH₂)_(n)NR₁R₂, where n is from 2 to 4. According to someembodiments, the pendant Lewis base derivative imparts biofunctionalityto the transition metal complex, when the transition metal complex isused as a catalyst.

According to some embodiments, transition metal complexes of type 3 arerepresented by the formula Φ-[M (x,y)-L₁ (w,v)-L₂XY]^((p+a)+)An⁻ _(m)Z⁻_(p-m), where Φ is Λ or Δ, wherein M is a transition metal, where p isan integer corresponding to the oxidation state of M, where each of x,y, w, and v is independently R or S, wherein each of L₁, and L₂comprises a chelating ligand comprising at least two nitrogens, where pis an integer corresponding to the oxidation state of M, wherein each ofL₁ and L₂ independently comprises a chelating ligand comprising at leasttwo metal coordinating atoms, where Y comprises a mono-coordinateddiamine ligand, where X comprises one out of a second mono-coordinateddiamine ligand and a nucleophilic ligand, where a is the total charge ofthe mono-coordinated ligand(s), where An⁻ represents a lipophilic anion,where m is from 1 to p, and where Z⁻ represents a second optional anion.Suitable chelating ligands include, but are not limited to, chelatingligands comprising at least two nitrogen atoms. According to someembodiments, the mono-coordinated ligand is chiral. The chirality may be(S)- or (R)-.

Suitable transition metals include, but are not limited to, cobalt (Co),iron (Fe), nickel (Ni), chromium (Cr), manganese (Mn), molybdenum (Mo),tungsten (W), rhenium (Re), ruthenium (Ru), technetium (Tc), osmium(Os), rhodium (Rh), iridium (Jr), platinum (Pt), and palladium (Pd). Forexample, according to some embodiments the transition metal is cobalt,iron, or nickel. Cobalt, iron, and nickel have the advantage of lowcost. In some embodiments, the transition metal is cobalt. Suitableoxidation states of the transition metal include, but are not limitedto, M(III) and M(IV).

Suitable lipophilic anions include, but are not limited to,tetrakis[(3,5-trifluromethyl)phenyl]borate);tetrakis[pentafluorophenyl]borate; carboranes of the general formulaCB₁₁H₁₂—, and its derivatives; TRISPHAT of the general formulaP(O₂C₆C₁₄)³⁻; and 1,1′-Binaphthyl-2,2′-diyl phosphates, and itsderivatives.

Suitable conventional anions include, but are not limited to, Cl⁻,perchlorate, and nitrate. The variable numbers p, m, n, a, b, and c areeach integers. According to some embodiments, the transition metalcomplex is in hydrated form.

Transition Metal Complexes of Type 1 The Stereochemistry of the ChiralLigand and the Chiral Metal Center

Referring to FIG. 1, for the metal complexes, there exist two possiblechiral configurations that center at the metal. These are called“chiral-at-metal centers” or “stereogenic metal centers”. Theconfigurations are named lambda (Λ) and delta (Δ). Representations ofeach configuration, Λ and delta Δ, are shown in FIG. 1, illustrated with3 (5,5)-DPEN ligands and cobalt (Co) metal. Thus, shown in FIG. 1 areΛ-[Co((S,S)-dpen)³]³⁺ and Δ-[Co((S,S)-dpen)₃]³⁺.

Referring to FIG. 2, for diphenylethylenediamine (DPEN), 3 possiblestereoisomeric arrangements are possible; (5,5)-DPEN, (R,R)-DPEN, and(S,R)-DPEN. Note that (R,S)-DPEN is equivalent to (S,R)-DPEN so listingit here, or otherwise herein, as a separate species is redundant.

Referring to FIG. 3, for each possible combination of the 3 chelatingligands there are two configurations at the metal center: Λ and Δ.

It will be understood that it is possible to use combinations of these 3ligands within one compound, so the following list of compounds wouldalso be available (not shown): 1) Λ-[Co((S,S)-dpen)₂((R,R)-dpen)]³⁺; 2)Λ-[Co((S,S)-dpen)₂((S,R)-dpen)]³⁺; 3) Λ-[Co((R,R)-dpen)₂((S,S)-dpen)]³⁺;4) Λ [Co((R,R)-dpen)₂((S,R)-dpen)]³⁺; 5)Λ-[Co((S,R)-dpen)2((S,S)-dpen)]³⁺; 6) Λ-[Co((S,R)-dpen)2((R,R)-dpen)]³⁺;and 7) Λ-[Co((S,S)-dpen)((R,R)-dpen)((S,R)-dpen)]³⁺.

Further, it will be understood that for all of these Λ complexesmentioned above, the corresponding Δ complex would also be available.Thus, the following list of compounds would also be available (notshown): 1) Δ-[Co((S,S)-dpen)₂((R,R)-dpen)]³⁺; 2)Δ-[Co((S,S)-dpen)₂((S,R)-dpen)]³⁺; 3) Δ-[Co((R,R)-dpen)₂((S,S)-dpen)]³⁺;4) Δ [Co((R,R)-dpen)₂((S,R)-dpen)]³⁺; 5)Δ-[Co((S,R)-dpen)₂((S,S)-dpen)]³⁺; 6) Δ-[Co((S,R)-dpen)₂((R,R)-dpen)]³⁺;and 7) Δ-[Co((S,S)-dpen)((R,R)-dpen)((S,R)-dpen)]³⁺.

Other Transition Metals

Besides cobalt, the other transition metals that could be used in asimilar way in this catalysis include, but are not limited to, iron,nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium,technetium, osmium, rhodium, iridium, platinum, and palladium. Thus,according to some embodiments the transition metal is cobalt, iron,nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium,technetium, osmium, rhodium, iridium, platinum, or palladium. Forexample, according to some embodiments the transition metal is cobalt,iron, or nickel. Further, for example, according to some embodiments thetransition metal is cobalt.

Counteranions

It is desirable for these catalysts to be soluble in aprotic organicsolvents. This is accomplished by using counteranion pairings with thecationic cobalt complex that render the complex soluble in aproticorganic solvents. The counteranion pairings are an assembly of counteranion groups that render the cobalt cation soluble in organic solvents.

An Counteranions

Suitable assemblies use between 1 and 3 anions that are deemed,“lipophilic” or “organic soluble”. In some embodiments,BArf-(tetrakis[(3,5-trifluromethyl)phenyl]borate) is a suitable anion.Other suitable lipophilic anions include, but are not limited to;tetrakis[pentafluorophenyl]borate; carboranes of the general formulaCB₁₁H¹²⁻, and its derivatives; TRISPHAT of the general formulaP(O₂C₆C₁₄)³⁻; and 1,1′-Binaphthyl-2,2′-diyl phosphates, and itsderivatives.

Z Counteranions

Often only one or two “organic soluble” anions are required in thepackage of 3 anions to render the whole complex soluble in aproticorganic solvents. In this case, the other one to two anion spaces can befilled by any possible anion even if it is not considered “lipophilic”.Such anions include, but are not limited to; Hydride H—, Oxide O²⁻,Fluoride F⁻, Sulfide S²⁻, Chloride CF, Nitride N³⁻, Bromide Br⁻, IodideI⁻, Arsenate AsO₄ ³⁻, Phosphate PO₄ ³⁻, Arsenite AsO₃ ³⁻, Hydrogenphosphate HPO₄ ²⁻, Dihydrogen phosphate H₂PO⁴⁻, Sulfate SO₄ ²⁻, NitrateNO³⁻, Hydrogen sulfate HSO⁴⁻, Nitrite NO²⁻, Thiosulfate S₂O₃ ²⁻, SulfiteSO₃ ²⁻, Perchlorate ClO⁴⁻, Iodate IO³⁻, Chlorate ClO³⁻, Bromate BrO³⁻,Chlorite ClO²⁻, Hypochlorite OCl⁻, Hypobromite OBr⁻, Carbonate CO₃ ²⁻,Chromate Cra₄ ²⁻, Hydrogen carbonate or Bicarbonate HCO³⁻, DichromateCr₂O₇ ²⁻, Acetate CH₃COO⁻, formate HCOO⁻, Cyanide CN⁻, Amide NH2⁻,Cyanate OCN⁻, Peroxide O²²⁻, Thiocyanate SCN⁻, Oxalate C₂O₄ ²⁻,Hydroxide OH⁻, Permanganate MnO⁴⁻, Azide N³⁻, and tartrate C₄H₄O₆ ²⁻.Further suitable conventional anions include, but are not limited to,triflate OSO₃CF³⁻ and tetraflouroborate BF⁴⁻ and hexafluorophosphatePF6⁻.

Derivatives of the DPEN Ligand

It will be understood that derivatives of the above mentioned DPENligands may be used to make cobalt complexes. The stereochemistry rulesthat apply to the original DPEN ligands apply to the derivatives below.Further, the stereochemistry rules that apply to the metal centers ofthese complexes formed by the addition of these DPEN derivatives are thesame as described above. For example, suitable DPEN derivatives include,but are not limited to, (S,S,)-, (R,R)-, and (S,R)-versions of2-bis-(4-methoxyphenyl)-1,2-diaminoethane;2-bis-(4-chlorophenyl)-1,2-diaminoethane;2-bis-(4-trifluoromethylphenyl)-1,2-diaminoethane;2-bis-(4-nitrophenyl)-1,2-diaminoethane;2-bis-(1-napthyl)-1,2-diaminoethane;2-bis-(2-napthyl)-1,2-diaminoethane;1,2-bis(2-methoxyphenyl)ethane-1,2-diamine;1,2-bis(3-methoxyphenyl)ethane-1,2-diamine;1,2-bis(2-methylphenyl)ethane-1,2-diamine;1,2-bis(3-methylphenyl)ethane-1,2-diamine;1,2-bis(4-methylphenyl)ethane-1,2-diamine;1,2-di(pyridin-2-yl)ethane-1,2-diamine;1,2-di(pyridin-3-yl)ethane-1,2-diamine;1,2-di(pyridin-4-yl)ethane-1,2-diamine;1,2-bis-(4-methoxyphenyl)-1,2-diaminoethane;1,2-bis-(4-chlorophenyl)-1,2-diaminoethane;1,2-bis-(4-trifluoromethylphenyl)-1,2-diaminoethane;1,2-bis-(4-nitrophenyl)-1,2-diaminoethane;1,2-bis-(1-napthyl)-1,2-diaminoethane; and1,2-bis-(2-napthyl)-1,2-diaminoethane.

Other Ligands

It will be understand that other substituted diamines may be used tomake the complex. Referring to FIG. 32, the substituted diamine may becyclohexanediamine.

Transition Metal Complexes of Type 2 Stereochemistry of the ChiralLigand and the Chiral Metal Center

Referring to FIG. 8, various cobalt amine complexes having the followingcationic backbone can be prepared using a substituted chiral ethylenediamine ligands having a pendant Lewis base in its side arm. Stillreferring to FIG. 8, X is the amount of the substituted chiral ethylenediamine ligands having a pendant Lewis base in its side arm.

Referring to FIG. 9, a series of substituted chiral ethylene diamineligands, having pendant Lewis base in its side arm can be synthesized.In particular, the ligand may be EN(CH₂)_(n)NR₁R₂.

Referring to FIG. 10, these ligands can have (S) configuration and (R)configuration at the chiral center. Referring to FIG. 11, for theseligands, the length of the tether can be varied and a wide variety ofbasic functional moieties can be incorporated to tune the basicity ofthe Lewis base.

When X=1

Referring to FIG. 12, when the ligand has (S) configuration in thechiral center, n=3 and R1=R2=Me, then the cobalt complex (X=1) can existas two stereoisomers (or diastereomers) which are shown in thefollowing.

Referring to FIG. 13, similarly, with the ligand which has (R)configuration in the chiral center, the cobalt complexes also show Λ andΔ stereoisomers (or diastereomers).

When X=2

Referring to FIG. 14, when the ligand has (S) configuration in thechiral center, n=3 and R1=R2=Me, then the cobalt complex (X=2) may havesix stereoisomers (or diastereomers). The three Λ isomers are shown onthe left and three Λ isomers are shown on the right.

The cobalt complex (X=2) may also have six stereoisomers (ordiastereomers) when the same ligand with (R) configuration at the chiralcenter has been used.

When X=3

Referring to FIG. 15, four different stereoisomers (or diastereomers)are possible when cobalt is attached to three ligands (X=3) with (S)configuration in the chiral center, n=3 and R1=R2=Me, which are shown inthe following.

Four other stereoisomers (or diastereomers) of the cobalt complex mayalso be possible when the same ligand with (R) configuration at thechiral center has been used.

Other Transition Metals

Besides cobalt, the other transition metals that could be used in asimilar way in this catalysis include, but are not limited to, iron,nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium,technetium, osmium, rhodium, iridium, platinum, and palladium. Thus,according to some embodiments, the transition metal is cobalt, iron,nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium,technetium, osmium, rhodium, iridium, platinum, or palladium. Forexample, according to some embodiments, the transition metal is cobalt,iron, or nickel. Further, for example, according to some embodiments,the transition metal is cobalt.

The Counteranions

It is desirable for these catalysts to be soluble in aprotic organicsolvents. This is accomplished by using counteranion pairings with thecationic cobalt complex that render the complex soluble in aproticorganic solvents. The counteranion pairings are an assembly of counteranion groups that render the cobalt cation soluble in organic solvents.

An Counteranions

Suitable assemblies use between 1 and 3 anions that are deemed“lipophilic” or “organic soluble”.BArf-(tetrakis[(3,5-trifluromethyl)phenyl]borate) is a suitable anion.Further, other suitable lipophilic anions include, but are not limitedto; tetrakis[pentafluorophenyl]borate; carboranes of the general formulaCB₁₁H¹²⁻, and its derivatives; TRISPHAT of the general formulaP(O₂C₆Cl₄)³⁻; and 1,1′-Binaphthyl-2,2′-diyl phosphates, and itsderivatives.

Z Counteranions

Often only one or two “organic soluble” anions are required in thepackage of 3 anions to render the whole complex soluble in aproticorganic solvents. In this case, the other one to two anion spaces can befilled by any possible anion even if it is not considered “lipophilic”.Such anions include, but are not limited to; Hydride H⁻, Oxide O²⁻,Fluoride F⁻, Sulfide S²⁻, Chloride Cl⁻, Nitride N³⁻, Bromide Br⁻, IodideI⁻, Arsenate AsO₄ ³⁻, Phosphate PO₄ ³⁻, Arsenite AsO³³⁻, Hydrogenphosphate HPO₄ ²⁻, Dihydrogen phosphate H₂PO⁴⁻, Sulfate SO4²⁻, NitrateNO³⁻, Hydrogen sulfate HSO⁴⁻, Nitrite NO²⁻, Thiosulfate S₂O₃ ²⁻, SulfiteSO₃ ²⁻, Perchlorate ClO⁴⁻, Iodate IO³⁻, Chlorate ClO³⁻, Bromate BrO³⁻,Chlorite ClO²⁻, Hypochlorite OCl⁻, Hypobromite OBr⁻, Carbonate CO₃ ²⁻,Chromate CrO₄ ²⁻, Hydrogen carbonate or Bicarbonate HCO³⁻, DichromateCr₂O₇ ²⁻, Acetate CH₃COO⁻, formate HCOO⁻, Cyanide CN⁻, Amide NH2⁻,Cyanate OCN⁻, Peroxide O²²⁻, Thiocyanate SCN⁻, Oxalate C₂O₄ ²⁻,Hydroxide OH⁻, Permanganate MnO⁴⁻, Azide N³⁻, and tartrate C₄H₄O₆ ²⁻.Further suitable conventional anions include, but are not limited to,triflate OSO₃CF³⁻, tetraflouroborate BF⁴⁻ and hexafluorophosphate PF6⁻.

Transition Metal Complexes of Type 3 Stereochemistry of the Chiral MetalCenter

Referring to FIG. 30, the minimum requirement for there to be a “chiralmetal center” or “stereogenic metal center” is for an octahedral (6binding sites) metal complex to have 2 chelating ligands in the cisconfiguration (chelating means one ligand binds at two different sites).The metal is a chiral center in the cis configuration whenever X=Y orwhen X≠Y.

Referring to FIG. 31, the complex with trans configuration is neverconsidered a “chiral-at-metal” center. However, if X or Y is a ligandwith a chiral center then the whole complex is considered chiral.

Hierarchy of Chiral Metal Complexes

Referring to FIG. 32, a pictorial example of possible arrangements ofligands coordinated to a metal is shown. Each level with a chiral metalis drawn as A but may also exist as A. Each chiral backbone (chelatingligand) is drawn as (R,R) but could also exist as (R,S) and (S,S).Finally, each ligand that has a stereocenter is drawn as (S) but couldalso be drawn as (R).

Chelating Ligand

Referring to FIGS. 33 and 34, the chelating ligand can take severalshapes. The unifying theme is that the ligand has at least 2 nitrogenatoms. Nitrogen is illustrative of a metal coordinating element. Thus,the ligand may have at least 2 metal coordinating atoms.

Ligands X and Y

The X and Y ligands may be the same or they may be different. At leastone of X and Y is a diamine. In some embodiments, one amine of thediamine coordinates to the metal while the other amine remainsuncoordinated.

Referring to FIGS. 35 and 36, examples of these ligands are shown. Thediamine can be achiral (FIG. 35) or chiral (FIG. 36). One unifying themeis that the two amines in one diamine ligand are different. One of theseis a primary amine (1° amine) because it is bonded to 1 carbon and 2hydrogens. The other amine on the ligand is a tertiary amine (3° amine)because it is bonded to 3 carbons. Ligands with a 1° amine and 2° amine(bonds to 2 carbons and 1 hydrogen) are also contemplated.

Metal Complexes

FIG. 37 represents a typical complex. In this embodiment, for anycombination of ligands X and Y, there are only two possibleconfigurations Λ and Δ. The remaining X ligand can be anything includinganother 1°/3° amine ligand. In some embodiments, this X spot is occupiedby chloride (Cl⁻) or ammonia (NH₃).

Other Transition Metals

Besides cobalt, the other transition metals that could be used in asimilar way in this catalysis include, but are not limited to, iron,nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium,technetium, osmium, rhodium, iridium, platinum, and palladium. Thus,according to some embodiments the transition metal is cobalt, iron,nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium,technetium, osmium, rhodium, iridium, platinum, or palladium. Forexample, according to some embodiments, the transition metal is cobalt,iron, or nickel. Further, for example, according to some embodiments,the transition metal is cobalt.

The Counteranions

It is desirable for these catalysts to be soluble in aprotic organicsolvents. This is accomplished by using counteranion pairings with thecationic cobalt complex that render the complex soluble in aproticorganic solvents. The counteranion pairings are an assembly of counteranion groups that render the cobalt cation soluble in organic solvents.

An Counteranions

Suitable assemblies use between 1 and 3 anions that are deemed“lipophilic” or “organic soluble”. BArf(tetrakis[(3,5-trifluromethyl)phenyl]borate) is a suitable anion.Further, other suitable lipophilic anions include, but are not limitedto; tetrakis[pentafluorophenyl]borate; carboranes of the general formulaCB₁₁H¹²⁻, and its derivatives; TRISPHAT of the general formulaP(O₂C₆C₁₄)³⁻; and 1,1′-Binaphthyl-2,2′-diyl phosphates, and itsderivatives.

Z Counteranions

In some embodiments, one or two “organic soluble” anions are required inthe package of 3 anions to render the whole complex soluble in aproticorganic solvents. In such embodiments, the other one to two anion spacescan be filled by any possible anion even if it is not considered“lipophilic”. Such anions include, but are not limited to; Hydride H⁻,Oxide O²⁻, Fluoride F⁻, Sulfide S²⁻, Chloride Cl⁻, Nitride N³⁻, BromideBr⁻, Iodide I⁻, Arsenate AsO₄ ³⁻, Phosphate PO₄ ³⁻, Arsenite AsO³³⁻′Hydrogen phosphate HPO4²⁻, Dihydrogen phosphate H2PO⁴⁻, Sulfate SO4²⁻,Nitrate NO³⁻, Hydrogen sulfate HSO⁴⁻, Nitrite NO²⁻, Thiosulfate S₂O³²⁻,Sulfite SO³²⁻, Perchlorate ClO⁴⁻, Iodate IO³⁻, Chlorate ClO³⁻, BromateBrO³⁻, Chlorite ClO²⁻, Hypochlorite OCl⁻, Hypobromite OBr⁻, CarbonateCO³²⁻, Chromate CrO⁴²⁻, Hydrogen carbonate or Bicarbonate HCO³⁻,Dichromate Cr₂O⁷²⁻, Acetate CH3COO⁻, formate HCOO⁻, Cyanide CN⁻, AmideNH²⁻, Cyanate OCN⁻, Peroxide O²²⁻, Thiocyanate SCN⁻, Oxalate C₂O₄ ²⁻,Hydroxide OH⁻, Permanganate MnO⁴⁻, Azide N³⁻, and tartrate C₄H₄O₆ ²⁻.Further suitable conventional anions include, but are not limited to,triflate OSO₃CF³⁻, tetraflouroborate BF⁴⁻ and hexafluorophosphate PF6⁻.

Applications and Advantages

The transition metal complexes of the present disclosure provide anattractive low cost catalyst system for the commercial manufacture ofenantiopure chemicals. In various embodiments, the transition metalcomplexes of the present disclosure are highly enantioselective andstable. Further, the transition metal complexes of the presentdisclosure can be synthesized and separated as pure diastereomers on agram scale. These have the added advantage of being easily tunableelectronic and steric factors with modified DPEN ligands. Further, thetransition metal complexes of the present disclosure demonstrate uniquefeatures compared to other hydrogen bond mediated catalysts, for exampleimproved function in polar solvents or aqueous media.

ADDITIONAL EMBODIMENTS

Reference will now be made to various embodiments of the presentdisclosure and experimental results that provide support for suchembodiments. Applicants note that the disclosure herein is forillustrative purposes only and is not intended to limit the scope of theclaimed subject matter in any way.

Example 1 Type 1 Transition Metal Complexes Preparation of DPEN LigandDerivatives

Referring to FIG. 4, a procedure to prepare derivatives of the DPENligand is illustrated. It is a general procedure that works to make alarge number of DPEN derivatives. In principle, the choice of aldehydeswith different variable groups (denoted as R) gives the differentderivatives of the DPEN ligand. It will be understood that there is morethan one procedure to prepare these derivatives of the DPEN ligand. Theprocedure illustrated in FIG. 5 is slightly modified from that offeredby: Kim, H.; Nguyen, Y.; Yen, C. P. H.; Chagal, L.; Lough, A. J.; Kim,B. M.; Chin, J. J. Am. Chem. Soc. 2008, 130, 12184-12191.

Example 2 Preparation of Transition Metal Complexes

Referring to FIG. 5, a general procedure to prepare cobalt complexes isillustrated. Part A illustrates a procedure to form an intermediatecobalt complex with conventional anions from a precursor cobalt salt,where the anion of the intermediate cobalt complex is the same as theanion of the precursor cobalt salt. Part B illustrates a procedure toform a cobalt complex soluble in organic solvent by replacing at leastone of the conventional anions with a lipophilic anion.

Preparation of DPEN Ligand Derivatives Procedure A.

To a cloudy solution of 0.9 g (4.10 mmol) of1,2-bis(hydroxylphenyl)-1,2-diamonoethane in ethanol (30 mL) was added(9.84 mmol, 2.4 eq.) of the corresponding aldehyde. The resulting clearsolution was stirred at room temperature overnight during which time ayellow precipitate develops. The solid is collected by filtration,washed with ethanol, and dried in vacuum.

Or

Procedure B.

To a clear solution of 0.9 g (4.10 mmol) of1,2-bis(hydroxylphenyl)-1,2-diamonoethane in DMSO (30 mL) as added (9.84mmol, 2.4 eq.) of the corresponding aldehyde. The resulting mixture wasstirred at room temperature overnight and then the mixture was pouredinto distilled water (150 mL). The aqueous layer was extracted withdiethyl ether (3×100 mL) and the organic layers were dried over Na₂SO₄,filtered, and concentrated by rotovap. The resulting diimine was furtherdried by oil pump vacuum.

Example 3 Hydrolysis of the Diimine Products Formed by Either ProcedureA or B

The diimine products from either procedure A or B were dissolved in THF(30 mL) and aqueous HCl (3 mL, 12 M) was added. The mixture stirred atroom temperature for 3 hours then was partitioned between H₂O (100 mL)and CH₂Cl₂ (100 mL). The organic phase was removed and the aqueous phasewashed with CH₂Cl₂ (100 mL). The aqueous phase was made basic by slowaddition of 3 M NaOH. The resulting cloudy solution was extracted withCH₂Cl₂ (3×150 mL). The organic phases were dried over Na₂SO₄, filtered,and concentrated by rotovap. The resulting diamines are further dried byoil pump vacuum.

The following list of DPEN derivatives have been prepared by thismethod: (S,S)-2-bis-(4-methoxyphenyl)-1,2-diaminoethane (procedure A);(S,S)-2-bis-(4-chlorophenyl)-1,2-diaminoethane (procedure B)(S,S)-2-bis-(4-trifluoromethylphenyl)-1,2-diaminoethane (procedure B);(S,S)-2-bis-(4-nitrophenyl)-1,2-diaminoethane (procedure A);(S,S)-2-bis-(1-napthyl)-1,2-diaminoethane (procedure B); and(S,S)-2-bis-(2-napthyl)-1,2-diaminoethane (procedure B).

Example 4 Preparation of Transition Metal Complexes

Procedures for the synthesis of cobalt complexes are illustrated in theexample below. These 2 procedures are generally representative for anyDPEN ligand set (i.e. a DPEN ligand or DPEN derivative of anystereochemistry could be substituted in this procedure). The onlydifference between the two procedures is whether the end product is a Λor Δ metal complex.

Procedure 1. Λ-[Co(dpen)3](BArf)Cl2 (Λ-1)

Cobalt acetate tetrahydrate (0.601 g, 2.49 mmol) and (S,S)-dpen (1.61 g,7.60 mmol, 3.32 eq.) were dissolved in methanol (75 mL) and charcoal(0.1 g) was added. Air was passed through the vigorously stirredsuspension at room temperature for 16 hours. The suspension was filteredthrough a pad of celite and the bright orange filtrate was acidifiedwith aqueous HCl (2M, 2 mL). The solvents were gently evaporated in anoil bath at 45° C. under a stream of nitrogen until the volume reachedca. 10 mL. The remaining solid was suspended in methanol (30 mL) andwater (100 mL) and filtered. The residue was suspended and filteredthree times from hot acetone (30 mL) The bright orange solid was driedunder oil pump vacuum to yield the trichloride salt (0.708 g).

A portion of the orange solid (0.452 g) was suspended in dichloromethane(10 mL) and NaBArf (0.501 g, 0.5655 mmol) was added. The suspension wasmixed by sonication and the colorless dichloromethane rapidly turnedbright orange as a faint white precipitate of NaCl developed. The newsuspension was filtered and the filtrate loaded onto a silica gelcolumn. The sorbed orange band was washed with CH₂Cl₂ (100 mL) and thenwas eluted with 98.5/1.5 CH₂Cl₂:MeOH. A very faint green band elutesfirst followed by a singular intense orange band. The orange band iscollected and concentrated by rotary evaporation and further dried underoil pump vacuum for 15 hours to yield a bright orange solid (0.659 g).

1H NMR (CD₂Cl₂, 500 MHz) δ 8.30 (br s, NH, 6H), 7.74 (s, o-CH BArf-,8H), 7.56 (s, p-CH BArf-, 4H), 7.41 (t, 6.5 Hz, p-CH dpen, 6H), 7.35 (t,7.5 Hz, m-CH dpen, 12H), 7.30 (d, 8.0 Hz, o-CH dpen, 12H) 4.48 (s, CH,dpen, 6H), 3.82 (br s, NH, 6H), 2.18 (br s, H₂O, 3H), 1.80 (s, HOD, 3H).13C NMR (CD₂Cl₂, 125 MHz) for BArf-δ 161.7 (q, 1JBC=49.4 Hz, i), 134.8(s, o), 128.8 (q, 2JCF=31.0 Hz, m), 124.5 (q, 1JCF=270.9 Hz, CF3), 117.4(s, p), for dpen 133.9 (s), 130.7 (s), 130.1 (s), 127.4 (s), 63.0 (s,PhCHNH₂)

Procedure 2. Δ-[Co(dpen)3](BArf)Cl2

Cobalt perchlorate hexahydrate (0.233 g, 0.775 mmol) and S,S-dpen (0.496g, 2.33 mmol, 3.01 eq.) were dissolved in MeOH (50 mL) and charcoal (0.1g) was added. Air was passed through the vigorously stirred suspensionat room temperature for 16 hours. The mixture was filtered throughcelite and the filtrate acidified with HClO₄ (2 mL, 35% in H₂O). Themethanol was gently evaporated by heating in an oil bath to 45° C. undera stream of nitrogen. A brownish yellow precipitate developed when mostof the MeOH had been removed. A suspension was made by adding H₂O (100mL) which was filtered and washed with more H₂O (100 mL). The residuewas then dissolved in MeOH (50 mL) and sorbed on a Dowex cation exchangecolumn. The orange band was washed with 1:1 H₂O/MeOH (100 mL). Theorange band was eluted with increasing gradients of aqueous HCl inmethanol; 1M aq. HCl in MeOH (100 mL), 2M aq. HCl in MeOH (100 mL), 3Maq. HCl in MeOH (100 mL), 4M aq. HCl in MeOH (200 mL). At 4M HCl, theorange band elutes from the column. The collected fraction isconcentrated by a rotary evaporator equipped with a base trap to yield abright orange solid as the crude trichloride (0.155 g). A portion ofthis solid (0.103 g) was suspended in CH₂Cl₂ and NaBArf (0.109 g, 0.123mmol) was added. The mixture was sonicated for a few seconds and thesolution became bright orange as a faint white precipitate of NaCldeveloped. The mixture was filtered and the orange filtrate was loadedonto a silica gel column. The adsorbed orange band was washed withCH₂Cl₂ (100 mL) then eluted with CH₂Cl₂:MeOH 98.5/1.5. Two orange bandsseparated. The fast moving minor band was Λ-1. The slower moving majorband was collected and concentrated by rotary evaporation to a brightorange solid which was further dried under oil pump vacuum at roomtemperature for 15 hours to yield Δ-1 (0.108 g).

1H NMR (CD₂Cl₂, 500 MHz) δ 7.72 (s, o-CH BArf-, 8H), 7.55 (s, p-CHBArf-, 4H), 7.34-7.28 (m, o-, m-, p-dpen, 30H), 6.14 (br s, NH), 5.75(br s, NH), 4.30 (s, CH, dpen, 6H), 2.48 (br s H₂O and HDO, 11H) 13C NMR(CD₂Cl₂, 125 MHz) 13C NMR (CD₂Cl₂, 125 MHz) for BArf-δ 161.7 (q,1JBC=49.5 Hz, i), 134.7 (s, o), 128.8 (q, 2JCF=28.4 Hz, m), 124.5 (q,1JCF=270.9 Hz, CF3), 117.4 (s, p), for dpen 134.0 (s), 129.9 (s), 129.3(s), 127.3 (s), 65.8 (t, 2JCD=14.5 Hz, PhCHND₂).

Example 5 Examples of Comparison of Z Counteranions

1H NMR spectra of cobalt complexes in CD₂Cl₂ after BArf-metathesis wasobtained. Strong hydrogen bonding between one diastereotopic set of N—Hbonds and Cl⁻ may be shown by a large downfield shift in 1H NMR spectra.In comparison with Cl⁻′ weak hydrogen bond accepting anions such astriflate or tetraflouroborate leads to an upfield shift for these N—Hbonds.

Example 6 Procedures for Reactions Catalyzed Using Complexes

Referring to FIGS. 6A-6B and FIG. 7, the catalysts were used inillustrative bond forming reactions. Referring to FIGS. 6A-6B and FIG.7, the chirality of the metal center determines the major productenantiomer in each illustrative reaction. FIGS. 6A-6B show anillustrative carbon-carbon bond forming reaction. FIG. 7 shows anillustrative carbon-heteroatom bond forming reaction.

The following three procedures are representative of how the catalystsare used in a reaction. The main difference in the procedures 1a and 1bis the solvent and base used in the reaction; however the reactants arethe same. For procedure 2, the reactant has changed fromdimethylmalonate to diphenylphosphite. In any of these procedures, theexact catalyst can be interchanged without any change in the reactionprocedure. (For instance, in procedure 1, the A catalyst is used, butcould just as easily have used the A catalyst. Procedure 1 was used togenerate the results shown in FIG. 6A. Procedure 1b was used to generatethe results shown in FIG. 6B. Procedure 2 was used to generate theresults shown in FIG. 7.

General Procedure 1

An NMR tube was charged with a solution of trans-β-nitrostyrene (0.0054g, 0.036 mmol), dimethylmalonate (0.0045 mL, 0.043 mmol),Λ-[Co(dpen)3](BArf)Cl2 (0.0050 g, 0.0036 mmol), and cyclohexane (0.0025mL) in CD₂Cl₂ (0.4 mL). A 1H NMR of the bright orange solution wasobserved for a time=0 measurement. Then triethylamine (0.0045 mL, 0.036mmol) was added to the NMR tube and the reaction proceeded at roomtemperature. Reaction conversion was monitored by 1H NMR until >99%conversion was achieved (2 h). The reaction solution was diluted withCH₂Cl₂ (1 mL) and passed through a short plug of silica with 1:1EtOAc/hexanes (50 mL). The solvent was removed from the eluate by rotaryevaporation and the resulting residue was analyzed by chiral HPLC todetermine the enantiopurity of the desired product. (2 hours, >99%conversion, 80% ee R).

An NMR tube was charged with a solution of trans-β-nitrostyrene (0.0054g, 0.036 mmol), dimethylmalonate (0.0045 mL, 0.043 mmol),Δ-[Co(dpen)3](BArf)Cl2 (0.0050 g, 0.0036 mmol), and cyclohexane (0.0025mL) in CD₂Cl₂ (0.4 mL). A 1H NMR of the bright orange solution wasobserved for a time=0 measurement. Then triethylamine (0.0045 mL, 0.036mmol) was added to the NMR tube and the reaction proceeded at roomtemperature. Reaction conversion was monitored by 1H NMR until >99%conversion was achieved (2 h). The reaction solution was diluted withCH₂Cl₂ (1 mL) and passed through a short plug of silica with 1:1EtOAc/hexanes (50 mL). The solvent was removed from elute by rotaryevaporation and the resulting residue was analyzed by chiral HPLC todetermine the enantiopurity of the desired product. (2 hours, >99%conversion, 76% ee S).

General Procedure 1b

A vial is charged with a solution of trans-β-nitrostyrene (0.0054 g,0.036 mmol), dimethylmalonate (0.0045 mL, 0.043 mmol),Λ-[Co(dpen)3](BArf)Cl₂ (0.0050 g, 0.0036 mmol), and hexadecane (0.0025mL) in CH₂Cl₂ (0.4 mL). An aliquot is removed from the mixture for atime=0 GC measurement. The bright orange solution is cooled to 0° C. anda solution of Na2CO3 (0.00038 g, 0.0036 mmol) in H₂O (0.15 mL) is added.The biphasic mixture is stirred at 0° C. for 12 hours and the conversionis measured by analyzing a removed aliquot by GC. The reaction solutionwas diluted with CH₂Cl₂ (1 mL) and passed through a short plug of silicawith 1:1 EtOAc/hexanes (50 mL). The solvent was removed from the eluateby rotary evaporation and the resulting residue was analyzed by chiralHPLC to determine the enantiopurity of the desired product. (12hours, >95% conversion, 90% ee R).

A vial is charged with a solution of trans-β-nitrostyrene (0.0054 g,0.036 mmol), dimethylmalonate (0.0045 mL, 0.043 mmol),Δ-[Co(dpen)3](BArf)Cl₂ (0.0050 g, 0.0036 mmol), and hexadecane (0.0025mL) in CH₂Cl₂ (0.4 mL). An aliquot is removed from the mixture for atime=0 GC measurement. The bright orange solution is cooled to 0° C. anda solution of Na₂CO₃ (0.00038 g, 0.0036 mmol) in H₂O (0.15 mL) is added.The biphasic mixture is stirred at 0° C. for 12 hours and the conversionis measured by analyzing a removed aliquot by GC. The reaction solutionwas diluted with CH₂Cl₂ (1 mL) and passed through a short plug of silicawith 1:1 EtOAc/hexanes (50 mL). The solvent was removed from the eluateby rotary evaporation and the resulting residue was analyzed by chiralHPLC to determine the enantiopurity of the desired product. (12hours, >99% conversion, 76% ee S).

General Procedure 2

An NMR tube is charged with a solution of trans-β-nitrostyrene (0.0054g, 0.036 mmol), diphenylphosphite (0.0086 mL, 0.045 mmol),Δ-[Co(dpen)3](BArf)Cl₂ (0.0050 g, 0.0036 mmol), and cyclohexane (0.0025mL) in CD₂Cl₂ (0.4 mL). A 1H NMR of the bright orange solution wasobserved for a time=0 measurement. Then triethylamine (0.0045 mL, 0.036mmol) was added to the NMR tube and the reaction proceeded at roomtemperature. Reaction conversion was monitored by 1H NMR until fullconversion was achieved (2 h). The reaction solution was diluted withCH₂Cl₂ (1 mL) and passed through a short plug of silica with 1:1EtOAc/hexanes (50 mL). The solvent was removed from the eluate by rotaryevaporation and the resulting residue was analyzed by chiral HPLC todetermine the enantiopurity of the desired product. (1 hour, >99%conversion, 73% ee S).

An NMR tube is charged with a solution of trans-β-nitrostyrene (0.0054g, 0.036 mmol), diphenylphosphite (0.0086 mL, 0.045 mmol),Λ-[Co(dpen)3](BArf)Cl₂ (0.0050 g, 0.0036 mmol), and cyclohexane (0.0025mL) in CD₂Cl₂ (0.4 mL). A 1H NMR of the bright orange solution wasobserved for a time=0 measurement. Then triethylamine (0.0045 mL, 0.036mmol) was added to the NMR tube and the reaction proceeded at roomtemperature. Reaction conversion was monitored by 1H NMR until fullconversion was achieved (2 h). The reaction solution was diluted withCH₂Cl₂ (1 mL) and passed through a short plug of silica with 1:1EtOAc/hexanes (50 mL). The solvent was removed from the eluate by rotaryevaporation and the resulting residue was analyzed by chiral HPLC todetermine the enantiopurity of the desired product. (1 hour, >99%conversion, 68% ee R).

Example 7 Type 2 Transition Metal Complexes Synthesis of Ligands

Different chiral ethylenediamine derivatives having different numbers ofcarbon atoms (n=2, 3) in the basic arms have been synthesized. Also, theligand (n=3) with cycloalkylamine as Lewis base was also synthesized.The synthetic schemes are shown in the following.

Referring to FIG. 16, synthesis of the salt of the ligand(S)—N5,N5-dimethylpentane-1,2,5-triamine (n=3) is illustrated.

Referring to FIG. 17, the hydrochloric acid salt of the(S)-5-(pyrrolidin-1-yl)pentane-1,2-diamine is illustrated. This salt ofthe ligand may be synthesized according to scheme 1 substitutingdimethylamine by pyrrolidine during amination.

Referring to FIG. 18, the synthesis of the hydrochloric acid salt of(S)—N4,N4-dimethylbutane-1,2,4-triamine (n=2) is illustrated.

The procedures for the synthesis of ligands were adapted from Ghosh, A.K.; Leshchenko-Yashchuk, S.; Anderson, D. D.; Baldridge, A.; Noetzel,M.; Miller, H. B.; Tie, Y. F.; Wang, Y.-F.; Koh, Y.; Weber, I. T.;Mitsuya, H. J. Med. Chem. 2009, 52, 3902; Altman, J.; Ben-Ishai, D.Tetrahedron: Asymmetry 1993, 4, 91; and Ganzmann, C. Doctorate Thesis,Universitat Erlangen-NUrnberg, 2010.

Example 8 Synthesis of the hydrochloric acid salt of(S)—N5,N5-dimethylpentane-1,2,5-triamine (n=3) (a)(5)-(5-oxopyrrolidin-2-yl)methyl-4-methylbenzenesulfonate 1

A round bottom flask was charged with(S)-5-(hydroxymethyl)-2-pyrrolidinone (9.5 g, 82.6 mmol),p-toluenesulfonyl chloride (19.0 g, 100 mmol), and CH₂Cl₂ (200 mL), andcooled to 0° C. DMAP (2.12 g, 17.34 mmol) and Et₃N (14 mL, 100.6 mmol)were added to the reaction mixture. The resulting mixture was allowed towarm to room temperature and stirred for overnight. The reaction wasthen quenched with 150 mL of water, and the aqueous layer was extractedwith CH₂Cl₂. The combined organic extracts were washed with 1 N HCl anddried over anhydrous Na₂SO₄. Removal of solvent under reduced pressurefollowed by flash chromatography purification (100% EtOAc as the eluent)yielded (S)-(5-oxopyrrolidin-2-yl) methyl-4-methylbenzenesulfonate(18.43 g, 68.5 mmol, 79%) as a white solid.

1H NMR (500 MHz, CDCl3, δ in ppm): 1.72-1.79 (m, 1H), 2.19-2.31 (m, 3H),2.44 (s, 3H), 3.85-3.92 (m, 2H), 4.02-3.99 (m, 1H), 6.53 (s, 1H), 7.35(d, 2H, J=5.0 Hz), 7.77 (d, 2H, J=10 Hz); 13C NMR (125 MHz, CDCl3, δ inppm): 21.6, 22.7, 29.2, 52.6, 71.9, 121.9, 127.8, 127.6, 130.0, 132.3,145.3, 117.9.

(b) (S)-5-(azidomethyl) pyrrolidin-2-one1

A round bottom flask was charged with(S)-(5-oxopyrrolidin-2-yl)methyl-4-methylbenzenesulfonate (18.4 g, 68.5mmol), DMF (400 mL), and NaN₃ (17.8 g, 274 mmol). The resulting mixturewas stirred at 55° C. for overnight. Removal of solvent under reducedpressure followed by flash chromatography purification (7% MeOH in CHCl3as the eluent) provided the (S)-5-(azidomethyl) pyrrolidin-2-one (8.45g, 60.36 mmol, 88%) as a yellow oil.

1H NMR (500 MHz, CDCl₃, δ in ppm): 1.78-1.83 (m, 1H), 2.21-2.39 (m, 3H),3.27-3.31 (dd, 1H, J=5 Hz, 15 Hz), 3.43-3.47 (dd, 1H, J=5 Hz, 15 Hz),3.78-3.83 (m, 1H), 7.00 (s, 1H); 13C NMR (125.6 MHz, CDCl₃, δ in ppm):24.0, 29.7, 53.5, 55.9, 178.4.

(c) (S)-5-(aminomethyl) pyrrolidin-2-one1

A round bottom flask was charged with the (S)-5-(azidomethyl)pyrrolidin-2-one (8 g, 57.14 mmol), EtOAc (400 mL). Pd/C (750 mg) wasadded to the reaction mixture. The mixture was stirred at roomtemperature under a hydrogen filled balloon for overnight, then filteredover Celite, and washed with EtOAc and MeOH. Removal of solvent underreduced pressure followed by flash chromatography purification (15% MeOHin CHCl₃ as the eluent) afforded the corresponding (S)-5-(aminomethyl)pyrrolidin-2-one (4.9 g, 42.98 mmol, 75%) as a yellow oil.

1H NMR (500 MHz, CDCl₃, δ in ppm): 1.87 (br s, 2H), 1.62-1.68 (m, 1H),2.07-2.13 (m, 1H), 2.21-2.27 (m, 2H), 2.60-2.56 (dd, 1H, J=5 Hz, 15 Hz),2.74-2.78 (dd, 1H, J=5 Hz, 15 Hz), 3.57-3.62 (m, 1H), 7.79 (br s, 1H).13C NMR (125.6 MHz, CDCl₃, δ in ppm): 24.4, 30.1, 47.8, 56.7, 179.0.

(d) (S)-4-carboxybutane-1,2-diaminium chloride2

A round bottom flask was charged with(S)-5-(aminomethyl)pyrrolidin-2-one (9.0 g, 79 mmol) and 400 mL of 6MHCl. The reaction mixture was heated to reflux for 20 h. The solvent wasevaporated to dryness and the resulting solid was washed withMeOH-diethyl ether. Then the white solid was dried in vacuum to yield(S)-4-carboxybutane-1, 2-diaminium chloride (15.75 g, 76.8 mmol, 97%).

1H NMR (500 MHz, D₂O, δ in ppm): 1.83-1.99 (m, 2H); 2.48-2.45 (t, 2H);3.20-3.19 (d, 2H); 3.59-3.53 (m, 1H); 13C NMR (125.6 MHz, D₂O, δ inppm): 27.7, 31.9, 43.3, 51.5, 178.9

(e) (S)-4,5-bis((isobutoxycarbonyl)amino)pentanoic acid2

A round bottom flask was charged with (S)-4-carboxybutane-1,2-diaminiumchloride (9.5 g, 46 mmol) and water (45 mL). The solution wasneutralized with 1M KOH (145 mL) and cooled in an ice-bath.Simultaneously, from two separate additional funnels, isobutyrylchloroformate (13.3 mL) in THF (190 mL) and 1M KOH (145 mL) were slowlyadded. The mixture was stirred for 1 h at 0° C. and overnight at roomtemperature. THF was removed in vacuum and the water layer was extractedwith EtOAc. The water layer was acidified with 2M HCl and extracted withEtOAc. The combined extract was dried over anhydrous Na₂SO₄. Removal ofsolvent under reduced pressure, gave 15.03 g (45.3 mmol, 98%) of(S)-4,5-bis((isobutoxycarbonyl)amino)pentanoic acid as white solid.

1H NMR (500 MHz, CDCl₃, δ in ppm): 0.88-0.89 (d, 12H); 1.74-1.89 (m,4H); 2.42-2.57 (m, 2H), 3.28 (m, 2H), 3.74-3.81 (m, 5H), 5.22-5.30 (br,2H).

(f) (S)-diisobutyl (5-hydroxypentane-1,2-diyl)dicarbamate3

A round bottom flask was charged with crudeS)-4,5-bis((isobutoxycarbonyl)amino)pentanoic acid (14.22 g, 42.84 mmol)and 1,2-dimethoxyethane (70 mL). N-methyl morpholine (5.24 mL, 47.1mmol) was added with stirring and the resulting solution was cooled to−25° C. Then isobutyl chloroformate (6.8 mL, 51.4 mmol) was added slowlyand a white precipitate formed. The cold bath was removed, and themixture was allowed to warm to room temperature. The precipitate wascollected by filtration and washed with 1,2-dimethoxyethane (2×30 mL).The combined filtrate and washings were deoxygenated with a stream ofnitrogen, and a solution of NaBH₄ (2.43 g, 64.3 mmol) in EtOH (150 mL)was added dropwise at 0° C. After 2 h, water (10 mL) was cautiouslyadded. The mixture was stirred overnight and the 0° C. bath was allowedto warm to room temperature. The solvent was removed by rotaryevaporation. The resulting solid was dissolved in EtOAc (300 mL) andwater (200 mL) was added. The aqueous phase was extracted with EtOAc(2×100 mL) and the combined organic phases were dried on anhydrousNa₂SO₄. The solvent was removed by rotary evaporation and the crudeproduct was purified on a silica gel column (1:1 v/v EtOAc/Hexane). Thesolvent was removed and dried in vacuum to give (S)-diisobutyl(5-hydroxypentane-1,2-diyl)dicarbamate as a white solid (11.13 g, 35mmol, 82%).

1H NMR (500 MHz, CDCl₃, δ in ppm): 5.17 (br s, 1H), 5.06 (br s, 1H),3.90-3.76 (m, 4H), 3.75-3.59 (t, 3H), 3.36-3.18 (m, 2H), 1.97-1.81 (m,2H), 1.69-1.56 (m, 3H), 1.55-1.43 (m, 1H), 0.97-0.86 (m, 12H). 13C NMR(125.6 MHz, CDCl₃, δ in ppm): 157.6, 157.3, 71.1, 62.4, 51.7, 45.1,29.2, 28.6, 28.0, 19.0.

(g) (S)-4,5-bis((isobutoxycarbonyl)amino)pentyl methanesulfonate3

A round bottom flask was charged with (S)-diisobutyl(5-hydroxypentane-1,2-diyl)dicarbamate (5.0 g, 15.7 mmol), CH₂Cl₂ (80mL), and triethylamine (5.3 mL, 38 mmol), and cooled to 78° C.Methanesulfonyl chloride (2.3 mL, 30 mmol) was added dropwise withstirring and the cold bath was allowed to warm to 0° C. over the courseof 5 h. Aqueous citric acid (20%, 140 mL) and CH₂Cl₂ (150 mL) were addedand the phases were separated. The organic phase was washed withsaturated NaHCO₃ solution, and then dried on anhydrous Na₂SO₄. Thesolvent was removed by rotary evaporation and dried in oil pump vacuum.The product (S)-4,5-bis((isobutoxycarbonyl)amino)pentyl methanesulfonatewas obtained as a yellowish white solid. The crude product was usedwithout further purification in the next procedure.

(h) (S)-diisobutyl-(5-(dimethylamino)pentane-1,2-diyl)dicarbamate3

An airfree round bottom flask was charged with the crude(S)-4,5-bis((isobutoxycarbonyl)amino)pentyl methanesulfonate from theprevious synthesis and a solution of HNMe₂ in THF (80 mL, 2.0 M). Thenthe stopper of the flask was tightened to stop the evaporation of HNMe₂during the reaction. The mixture was placed in an 80° C. oil bath. After15 h, the reaction mixture was cooled to room temperature and thesolvent was removed by rotary evaporation. The residue was dissolved inCH₂Cl₂ (200 mL), washed with saturated NaHCO₃ (150 mL) and brine (100mL), and dried on anhydrous Na₂SO₄. The solvent was removed by rotaryevaporation and the oily yellow residue was purified by a silica gelcolumn (with CH₂Cl₂/MeOH). The solvent was removed from theproduct-containing fractions to give (S)-diisobutyl-(5-(dimethylamino)pentane-1,2-diyl) dicarbamate as an oily yellow residue (4.66 g, 13.55mmol, 88% for two steps).

1H NMR (500 MHz, CDCl₃, δ in ppm): 5.71 (br s, 1H), 5.27 (br s, 1H),3.90-3.75 (d, J=10 Hz, 4H), 3.70-3.58 (m, 1H), 3.33-3.08 (m, 2H),2.30-2.23 (m, 2H), 2.20 (s, 6H), 1.96-1.79 (m, 2H), 1.62-1.38 (m, 4H),0.97-0.82 (m, 12H). 13C NMR (125.6 MHz, CDCl3, δ in ppm): 157.4, 157.3,71.0, 59.1, 51.5, 45.4, 45.2, 30.4, 28.0, 23.6, 19.0.

(i) Hydrochloric acid salt of (S)—N5,N5-dimethylpentane-1,2,5-triamine

A round bottom flask was charged with(S)-diisobutyl-(5-(dimethylamino)pentane-1,2-diyl)dicarbamate (4.2 g,12.2 mmol) and 6.0 M HCl (250 mL), and the solution was refluxed for 36h. The acidic solvent was evaporated in vacuum and the hydrochloridesalt of (S)—N5,N5-dimethylpentane-1,2,5-triamine was obtained as stickysolid with 71% yield (2.994 g, 8.7 mmol). The compound was highlyhygroscopic.

1H NMR (500 MHz, D₂O, δ in ppm): 1.84-1.58 (m, 4H); 2.76 (s, 6H);3.12-3.03 (m, 2H), 3.24-3.21 (m, 2H); 3.60-3.55 (m, 1H). 13C NMR (125.6MHz, D2O, δ in ppm): 22.6, 29.6, 41.07, 43.1, 45.4, 51.6, 59.2.

Example 9 Synthesis of hydrochloride salt of(S)—N4,N4-dimethylbutane-1,2,4-triamine (n=2) (a)(5)-diisobutyl-(5-amino-5-oxopentane-1,2-diyl)dicarbamate

A round bottom flask was charged with(S)-4,5-bis((isobutoxycarbonyl)amino)pentanoic acid (4.0 g, 12 mmol) andanhydrous THF (130 mL). N-methyl morpholine (1.7 mL, 15.4 mmol) wasadded with stirring and the resulting solution was cooled to −20° C.Then isobutyl chloroformate (2.0 mL, 15.4 mmol) was added slowly and themixture was stirred for 0.5 h. Conc. ammonium hydroxide (30%) (8.8 mL)was added and the mixture was stirred at −20° C. to 0° C. for 6 hoursand then evaporated to dryness. The residue was purified by silica gelcolumn chromatography using 7% (15% concentrated ammonium hydroxide inmethanol)-CH₂Cl₂ as eluent. The solvent was removed and dried in vacuumto give (S)-diisobutyl-(5-amino-5-oxopentane-1,2-diyl) dicarbamate as awhite solid (3.42 g, 10.2 mmol, 85%).

1H NMR (500 MHz, DMSO-d6, δ in ppm): 0.76-0.97 (m, 12H); 1.31-2.11 (m,5H); 2.84-3.04 (m, 2H), 3.33 (s, 1H), 3.37-3.6 (m, 1H), 3.62-3.74 (m,4H), 6.24-7.64 (br m, 4H).

13C{1H} NMR (125.6 MHz, DMSO-d6, δ in ppm): 174.0, 156.6, 156.2, 69.7,69.4, 50.6, 44.2, 31.7, 27.7, 27.5, 19.0, 18.9.

(b) (S)-diisobutyl (4-aminobutane-1,2-diyl)dicarbamate4

A round bottom flask was charged with(S)-diisobutyl-(5-amino-5-oxopentane-1,2-diyl)dicarbamate (3.0 g, 9mmol), CH₃CN (25 mL), EtOAc (25 mL), water (12 mL), and iodosobenzenediacetate (4.2 g, 13 mmol). The reaction mixture was stirred at roomtemperature. After 15 hours the solvents were evaporated and the crudemixture was purified by silica gel column chromatography (5% to 20% MeOHin CH₂Cl₂) to afford (S)-diisobutyl (4-aminobutane-1,2-diyl)dicarbamateas a colorless sticky liquid (1.55 g, 5.1 mmol, 57%).

1H NMR (500 MHz, CDCl₃, δ in ppm): 0.80-0.98 (d, 12H, J=5 Hz); 1.42-1.77(m, 2H), 1.79-1.99 (m, 2H); 2.70-2.91 (m, 2H), 3.36-3.08 (br s, 2H),3.82 (m, 5H), 5.2-5.60 (br, 2H). 13C NMR (125.6 MHz, CDCl₃, δ in ppm):157.5, 157.3, 71.1, 50.0, 45.2, 38.4, 35.6, 28.0, 28.0, 19.0.

(c) (S)-diisobutyl (4-(dimethylamino)butane-1,2-diyl)dicarbamate

A fisher porter bottle was charged with (S)-diisobutyl(4-aminobutane-1,2-diyl)dicarbamate (1.8 g, 6 mmol), methanol (50 mL)and distilled water (15 mL) and 37% aqueous formaldehyde (1.6 mL). Themixture was stirred for 1 h and 10% wet Pd—C(1.2 g) was added inportions and the mixture was hydrogenated at 50 psi for 24 h at RT. Themixture was filtered through a plug of Celite and washed withmethanol-distilled water (1:1). The solvent was removed and the residuewas chromatographed on a silica gel column (5% to 20% methanol in CH₂Cl₂to give (S)-diisobutyl (4-(dimethylamino)butane-1,2-diyl)dicarbamate(1.016 g, 51%) as colorless oil.

1H NMR (500 MHz, CDCl₃, δ in ppm): 0.80-1.02 (m, 12H); 1.52-1.99 (m,4H), 2.14-2.41 (m, 6H); 2.41-2.66 (m, 2H), 3.13-3.38 (m, 2H), 3.66-3.94(m, 5H), 5.36-6.12 (br, 2H). 13C NMR (125.6 MHz, CDCl₃, δ in ppm):157.7, 157.4, 72.1, 71.2, 71.1, 50.9, 50.7, 45.0, 29.2, 28.0, 28.0,19.9.

(d) Hydrochloride salt of (S)—N4,N4-dimethylbutane-1,2,4-triamine

A round bottom flask was charged with (S)-diisobutyl(4-(dimethylamino)butane-1,2-diyl)dicarbamate (0.9 g, 2.7 mmol) and 6 MHCl (50 mL). The reaction mixture was refluxed for 50 h. The acidicsolvent was evaporated in vacuum and the hydrochloride salt(S)—N4,N4-dimethylbutane-1,2,4-triamine was obtained as sticky solid(0.607 g). The compound was highly hygroscopic.

1H NMR (500 MHz, D₂O, δ in ppm): 2.39-2.18 (m, 4H); 2.96 (s, 6H),3.51-3.33 (m, 2H), 3.86-3.75 (m, 1H). 13C NMR (125.6 MHz, D₂O, δ inppm): 26.3, 41.2, 43.6, 47.8, 53.8.

Hydrochloride salt of (S)-5-(pyrrolidin-1-yl)pentane-1,2-diamine (n=3)

(S)-diisobutyl-(5-(pyrrolidin-1-yl)pentane-1,2-diyl)dicarbamate.

An air free round bottom flask was charged with the previouslysynthesized crude (S)-4,5-bis((isobutoxycarbonyl)amino)pentylmethanesulfonate (1.79 g, 4.52 mmol) and THF (15 mL). Pyrrolidine (3.7mL, 45.2 mmol) was added to the reaction mixture. Then the stopper ofthe flask was tightly closed. The mixture was placed in an 80° C. oilbath. After 15 h, the reaction mixture was cooled to room temperatureand the solvent was removed by rotary evaporation. The residue wasdissolved in CH₂Cl₂ (40 mL), washed with saturated NaHCO₃ (30 mL) andbrine (20 mL), and dried on anhydrous Na₂SO₄. The solvent was removed byrotary evaporation and the oily yellow residue was purified by a silicagel column (with CH₂Cl₂/MeOH). The solvent was removed from theproduct-containing fractions to give(S)-diisobutyl-(5-(pyrrolidin-1-yl)pentane-1,2-diyl)dicarbamate (1.45 g,4.08 mmol, 90%).

1H NMR (500 MHz, CDCl₃, δ in ppm): 5.99 (br s, 1H), 5.27 (br s, 1H),3.95-3.73 (d, J=10 Hz, 4H), 3.72-3.54 (m, 1H), 3.36-3.06 (m, 2H),2.58-2.29 (m, 6H), 1.94-1.80 (m, 2H), 1.79-1.75 (m, 4H), 1.66-1.38 (m,4H), 0.99-0.78 (d, J=15 Hz, 12H); 13C NMR (125.6 MHz, CDCl₃, δ in ppm):157.6, 157.5, 71.2, 71.1, 56.1, 54.1, 51.4, 45.6, 30.9, 28.1, 24.9,23.5, 19.2.

Example 10 Hydrochloride salt of the(S)-5-(pyrrolidin-1-yl)pentane-1,2-diamine

A round bottom flask was charged with(S)-diisobutyl-(5-(pyrrolidin-1-yl)pentane-1,2-diyl)dicarbamate (1.44 g,4.05 mmol) and 6.0 M HCl (70 mL), and the solution was refluxed for 30h. The acidic solvent was evaporated in vacuum and the hydrochloridesalt of (S)-5-(pyrrolidin-1-yl)pentane-1,2-diamine was obtained asyellowish sticky solid (1.30 g). The compound was highly hygroscopic.See FIG. 2b .15.

1H NMR (500 MHz, D₂O, δ in ppm): 3.77-3.62 (m, 3H); 3.44-3.32 (m, 2H);3.31-3.21 (m, 2H), 2.24-2.08 (m, 2H); 2.06-1.73 (m, 6H); 13C NMR (125.6MHz, D₂O, δ in ppm): 54.8, 54.4, 49.6, 41.1, 27.8, 23.2, 22.0.

Example 11 Synthesis of Metal Complexes

Synthesis and purification of cobalt complexes were adapted fromGanzmann, C. Doctorate Thesis, Universitat Erlangen-NUrnberg, 2010.

[Co(en)₂(S)-en CH₂CH₂CH₂NMe₂]³⁺3 BArf-

A round bottom flask was charged with [Co(en)₂CO₃]³⁺Cl⁻ (0.606 g, 2.21mmol), activated charcoal (0.440 g), and water (20 mL), and fitted witha condenser. The reaction mixture was heated to 40° C. Then thehydrochloric acid salt of (S)—N5,N5-dimethylpentane-1,2,5-triamine(0.519 g, 2.04 mmol) was added in one portion. The temperature wasincreased to 100° C. After 0.8 h, the activated charcoal was removed byfiltration and the red filtrate was evaporated to dryness by rotaryevaporation. The red solid was dissolved in 0.5 M HCl (100 mL), andsorbed on a Dowex (50WX2 hydrogen form, 200-400 mesh) column (4.2×15cm), which was eluted with 1.0 M (250 mL) followed by 2.0 M HClsolution. Three distinguishable orange bands were obtained. When thesecond orange band reached the column outlet, the eluent was changed to3.0 M HCl. The second orange band was collected, and evaporated todryness to give an orange solid (0.380 g).

Referring to FIG. 19, the orange solid was[Co(en)₂(S)-enCH₂CH₂CH₂NMe₂H]⁴⁺4Cl—.

1H NMR (500 MHz, D₂O, δ in ppm): 5.4-4.85 (br m, 10H), 4.64-4.37 (br m,2H) 3.27-3.13 (m, 2H), 3.12-2.69 (m, 16H), 2.66-2.59 (br s, 1H),2.01-1.72 (br m, 4H); 13C{1H} NMR (125.6 MHz, D₂O, δ in ppm): 58.4,57.6, 57.0, 49.6, 48.7, 45.6, 45.6, 45.5, 45.3, 45.3, 45.2, 45.0, 44.9,43.2, 29.2, 29.0, 22.0 (Dioxane as ref. at 67.14 ppm).

The orange solid obtained from second band of the Dowex column wasredissolved in 40 mL of water and sorbed in a SP Sephadex (C-25) column(4.4×44 cm). Two bands separated upon elution with 0.10 M (250 mL), 0.15M (250 mL), 0.20 M (500 mL) and 0.25 M 2Na+d-tart2-.2H₂O.

The first band from the Sephadex column was collected and concentratedto 100 mL. This solution was sorbed on a Dowex column. Then, thecompound was eluted by using 1 (M) to 3 (M) HCl solutions to give anorange solid (0.230 g).

Referring to FIG. 20, the first band gave(Co(en)₂(S)-enCH₂CH₂CH₂NMe₂H]⁴⁺4Cl-.3.5H₂H₂O. (Fr-1[Co(en)₂(S)-enCH₂CH₂CH₂NMe₂H]⁴⁺4Cl⁻.3.5H₂O).

1H NMR (500 MHz, D₂O, δ in ppm): 5.5-4.84 (br m, 10H), 4.69-4.43 (br m,2H) 3.26-3.13 (m, 2H), 3.11-2.69 (m, 18H), 2.66-2.49 (br s, 1H),2.04-1.67 (br m, 4H). 13C{1H} NMR (125.6 MHz, D₂O, δ in ppm): 58.4,57.6, 49.6, 45.5, 45.3, 45.3, 45.2, 43.2, 29.2, 29.0, 22.0. (Dioxane asref. at 67.14 ppm).

Similarly, the second band from the Sephadex column was collected andconcentrated to 100 mL. Then the solution was sorbed on a Dowex column.Then, the compound was eluted by using 1.0 (M) to 3.0 (M) HCl solutionsto give an orange solid (0.134 g).

Referring to FIG. 21, the second band gaveFraction-2-[Co(en)₂(S)-enCH₂CH₂CH₂NMe₂H]⁴⁺4Cl-.8H2O.

1H NMR (500 MHz, D₂O, δ in ppm): 5.4-5.26 (br s, 1H), 5.22-4.95 (br m,5H), 4.64-4.35 (br 2H), 3.27-3.08 (m, 3H), 3.07-2.48 (m, 16H), 2.66-2.59(br s, 1H), 1.98-1.68 (br m, 4H); 13C{1H} NMR (125.6 MHz, D₂O, δ inppm): 58.4, 57.0, 48.7, 45.6, 45.0, 44.9, 43.3, 29.1, 22.0 (Dioxane asref. at 67.14 ppm).

A round bottom flask was charged with Fraction 1-[Co(en)₂(S)-enCH₂CH₂CH₂NHMe₂]⁴⁺4Cl-.3.5H₂O (0.070 g, 0.134 mmol), aq. NaOH (1.5 mL,0.10 mmol), and water (10 mL). Then a solution of Na+ BArf-(0.335 g,0.361 mmol) in CH₂Cl₂ (20 mL) was added and the heterogeneous mixturewas vigorously stirred for 0.5 h. The orange organic phase was separatedfrom the aqueous phase and washed with water and allowed to evaporate inthe air to give Fraction-1 [Co(en)₂(S)-en CH₂CH₂CH₂NMe₂]³⁺3BArf-.6.5H₂Oas an orange powder (0.318 g).

Referring to FIG. 22, the orange powder is Fraction-1 [Co(en)₂(S)-enCH₂CH₂CH₂NMe₂]³⁺3BArf-.6.5H₂O.

1H NMR (500 MHz, DMF-d7, δ in ppm): 7.91-7.69 (m, 35H), 5.56-4.98 (m,10H), 4.73 (br s, 1H), 3.5 (s, 13H), 3.27 (br s, 1H), 3.15-2.93 (br s,7H), 2.29-2.07 (m, 14H), 1.84-1.41 (m, 4H). 13C{1H} NMR (125.6 MHz,CD₃CN, δ in ppm): 162.6 (q, 1JBC=49.6 Hz), 135.7 (s), 129.9 (q,2JCF=31.4 Hz), 125.5 (q, 1JCF=271.3 Hz), 118.7, 59.2, 50.1, 45.8, 45.6,45.3, 45.3, 30.3, 24.6.

A round bottom flask was charged with Fraction-2 [Co(en)₂(S)-enCH₂CH₂CH₂NMe₂]⁴⁺4Cl-.8H₂O (0.085 g, 0.143 mmol), aq. NaOH (1.5 mL, 0.1M), and water (15 mL). Then a solution of Na+ BArf-(0.371 g) in CH₂Cl₂(20 mL) was added and the heterogeneous mixture was vigorously stirredfor 0.5 h. The orange organic phase was separated from the aqueous phaseand the organic phase was washed with water and allowed to evaporate inthe air to give Fraction-2 [Co(en)²(S)-en CH²CH²CH²NMe²]³⁺3BArf-.15H₂Oas an orange powder.

Referring to FIG. 23, the second orange powder is Fraction-2[Co(en)₂(S)-en CH₂CH₂CH₂NMe₂]³⁺3 BArf-.15H₂O.

1H NMR (500 MHz, DMF-d7, δ in ppm): 7.86-7.70 (m, 48H), 5.78-5.02 (m,10H), 4.91-67 (br m, 2H), 3.51 (s, 30H), 3.36 (br s, 1H), 3.18-2.93 (brs, 9H), 2.4-1.95 (br s, 10H), 1.88-1.37 (m, 4H).

Co(en)₂(S)-en CH₂CH₂NMe₂]³⁺3BArf-

A round bottom flask was charged with [Co(en)₂CO₃]³⁺Cl— (0.606 g, 2.21mmol), activated charcoal (0.440 g), and water (20 mL), and fitted witha condenser. The reaction mixture was heated to 40° C. Then thehydrochloric acid salt of (S)—N4,N4-dimethylbutane-1,2,4-triamine (n=2)(0.494 g, 2.04 mmol) was added in one portion. The temperature wasincreased to 100° C. After 0.8 h, the activated charcoal was removed byfiltration and the red filtrate was evaporated to dryness by rotaryevaporation. The red solid was dissolved in 0.5 M HCl (100 mL), andsorbed on a Dowex (50WX2, 200-400 mesh) column (4.2×15 cm), which waseluted with 1.0 M (250 mL) followed by 2.0 M HCl. Three distinguishableorange bands were obtained. When the second orange band reached thecolumn outlet, the eluent was changed to 3.0 M HCl. The second orangeband was collected, and evaporated to dryness to give an orange solid(0.372 g).

Referring to FIG. 24, the orange solid was[Co(en)₂(S)-enCH₂CH₂NMe₂H]4+4Cl—.

1H NMR (500 MHz, D₂O, δ in ppm): 5.6-4.82 (br m, 9H), 4.75-4.38 (m, 1H),3.45-3.24 (m, 2H), 3.23-2.56 (m, 17H), 2.30-2.15 (m, 2H). 13C{1H} NMR(125.6 MHz, D₂O, 6 in ppm): 56.0, 55.9, 55.0, 54.8, 54.7, 49.5, 48.6,45.4, 45.3, 45.2, 45.1, 45.0, 43.5, 43.4, 43.3, 27.3.

The orange solid (0.300 g) obtained from second band of the Dowex columnwas redissolved in 40 ml of water and sorbed in a SP Sephadex (C-25)column (4.4×44 cm). Two bands separated upon elution with 0.10 M (1000mL), 0.15 M (1000 mL), 0.20 M (1000 mL) and of 0.25 M 2Na+d-tart2-.2H₂O.Each band was collected and concentrated.

The first band from the Sephadex column was collected and concentratedto 100 mL. This solution was sorbed on a Dowex column. Then, thecompound was eluted by using 1.0 (M) to 3.0 (M) HCl solutions to give anorange solid (0.181 g).

Referring to FIG. 25, the first band gave[Co(en)₂(S)-enCH₂CH₂NMe₂H]⁴⁺4Cl-.4H₂O.

1H NMR (500 MHz, D₂O, δ in ppm): 5.46 (br s, 1H), 5.27-4.84 (br m, 11H),3.46-3.23 (br m, 2H) 3.19-2.61 (m, 18H), 2.32-2.14 (m, 2H), 13C{1H} NMR(125.6 MHz, D₂O, δ in ppm): 55.76, 54.9, 49.2, 45.2, 45.1, 45.0, 44.9,43.5, 43.3 (Dioxane as ref. at 67.14 ppm).

The second band from the Sephadex column was collected and concentratedto 100 mL. This solution was sorbed on a Dowex column. Then, thecompound was eluted by using 1(M) to 3 (M) HCl solutions to give anorange solid (0.091 g).

Referring to FIG. 26, the second band gaveFraction-2-[Co(en)₂(S)-enCH₂CH₂NMe₂H]⁴⁺4Cl-.xH₂O.

1H NMR (500 MHz, D₂O, δ in ppm): 5.38 (br s, 1H), 5.27-5.05 (br m, 5H),4.74-4.66 (br m, 1H), 4.58-4.48 (br m, 1H), 3.49-3.33 (br m, 2H),3.32-3.20 (br m, 1H) 3.09-2.68 (m, 16H), 2.34-2.21 (m, 2H), 13C{1H} NMR(125.6 MHz, D₂O, δ in ppm): 55.0, 54.8, 48.6, 45.7, 45.6, 45.1, 45.0,43.4, 43.3 (Dioxane as ref. at 67.14 ppm).

A round bottom flask was charged with Fr 1-[Co(en)₂(S)-enCH₂CH₂NHMe₂]⁴⁺4 Cl-.4H₂O (0.051 g, 0.133 mmol), aq NaOH (1.5 mL, 0.1 M),and water (12 mL). Then a solution of Na+ BArf-(0.250 g) in CH₂Cl₂ (20mL) was added and the heterogeneous mixture was vigorously stirred for0.5 h. The orange organic phase was separated from the aqueous phase andthe organic phase was washed with water and allowed to evaporate in thehood to give Fr-1 [Co(en)₂(S)-en CH₂CH₂NMe₂]³⁺3 BArf-.12H₂O as an orangepowder (0.302 g).

Referring the FIG. 27, the orange powder was Fraction-1 [Co(en)₂(S)-enCH₂CH₂NMe₂]³⁺3BArf-.12H₂O.

1H NMR (500 MHz, CD₃CN, δ in ppm): 7.76-7.58 (m, 35H), 4.56-3.53 (br m,12H), 3.03-2.58 (br m, 10H), 2.56-2.44 (m, 2H), 2.40-2.29 (m, 1H),2.27-2.21 (br s, 24H), 2.19 (s, 1H), 1.91-1.86 (m, 1H), 1.75-1.65 (m,1H). 13C{1H} NMR (125.6 MHz, CD₃CN, δ in ppm): 162.6 (q, 1JBC=50.2 Hz),135.7 (s), 129.9 (q, 2JCF=31.4 Hz), 125.5 (q, 1JCF=271.3 Hz), 118.7,58.8, 56.7, 49.4, 45.7, 45.6, 45.3, 45.2, 28.2.

[Co((S)-enCH₂CH₂CH₂NMe₂H)₃]⁶⁺6Cl—

A round bottom flask was charged with a solution of CoCl₂.6H₂O (0.257 g,1.08 mmol, 1 eq) in 2.5 mL water. Then the hydrochloric acid salt of(S)—N5,N5-dimethylpentane-1,2,5-triamine (1.45 g, 4.3 mmol, 4 eq) wasadded with stirring. The mixture was stirred for 15 min. NaOH (0.550 g,12 eq) was added and the mixture was stirred until the NaOH dissolvedcompletely. The solution becomes dark red. 3% H₂O₂ solution (1.6 mL) wasadded with stirring. The solution became dark upon addition of peroxide.The mixture was diluted to 6.0 mL and boiled for 0.5 h. Then, 3.0 M HCl(1 mL) was added with stirring. After cooling to room temperature, thereaction mixture was evaporated to dryness. The residue was dissolved in1.0 (M) HCl (50 mL) and the mixture was sorbed on a Dowex column (4.2×15cm), which was eluted with 1.0 M HCl (250 mL) followed by 2.0 M HCl (250mL), 3.0 M HCl (250 mL) and 4.0 M HCl. The compound was collected byeluting with 4.0 M HCl and the orange to red colored solution wasevaporated to dryness to give a deep red solid (0.994 g) which was themixture of the diastereomers.

Referring to FIG. 28, the red solid was [Co((S)-enCH₂CH₂CH₂NMe₂H)3]⁶⁺6Cl—.

1H NMR (500 MHz, D₂O, δ in ppm): 5.47-4.86 (br m, 8H); 3.24-2.96 (br m,12H), 2.87 (s, 18H), 2.68-2.53 (br m, 3H), 2.68-2.53 (br m, 12H);13C{1H} NMR (125.6 MHz, D₂O, δ in ppm) 58.55/58.51/58.49/58.44,57.57/57.54, 49.62/49.61, 43.33/43.28, 28.97/28.87/28.86/28.84,21.99/21.97.

Example 12 Procedures for Reactions Catalyzed Using Type 2 TransitionMetal Complexes

The complexes Fraction-1 [Co(en)₂(S)-en CH₂CH₂CH₂NMe₂]³⁺3 BArf-.6.5H₂O,Fr-2 [Co(en)2(S)-en CH₂CH₂CH₂NMe₂]³⁺3BArf-.15H₂O, Fraction-1[Co(en)₂(S)-en CH₂CH₂NMe₂]³⁺3 BArf-.12H₂O were tested as catalysts inthe Michael addition of trans-β-nitrostyrene and diethyl malonate.

Referring to FIG. 29, results the catalyzed Michael addition oftrans-β-nitrostyrene and diethyl malonate ranged from 76-85% ee R usingFr-1 [Co(en)₂(S)-en CH₂CH₂CH₂NMe₂]³⁺3 BArf-.6.5H₂O.

The complex Fraction-1 [Co(en)₂(S)-en CH₂CH₂CH₂NMe₂]³⁺ 3BArf-.6.5H₂O wasfound to be the best catalyst, with higher yield and enantioselectivity,for the Michael addition of trans-β-nitrostyrene and diethyl malonate.

General Procedure for Michael Addition

A NMR tube was charged with β-nitrostyrene (0.0149 g, 0.10 mmol),diethyl malonate (0.0182 mL, 0.012 mmol), catalyst (7 mol %),1,2-dichloroethane (0.0080 mL, 0.10 mmol) as internal standard, andCD₂Cl₂ (0.4 mL). The NMR tube was sealed with a plastic cap andparafilm. The reaction was monitored by 1H NMR. The reaction solutionwas passed through a short pad of silica with hexanes and ethyl acetatemixture. The solvent was evaporated by rotary evaporation. Then theenantioselectivity for the reactions were measured by chiral HPLC.

Example 13 Type 3 Transition Metal Complexes Synthesis of MetalComplexes

Referring to FIG. 38, shown is a synthesis procedure for cobaltcomplexes having 1°/3° ligand (L).

Examples of Synthesis of Metal Complexes

The following experimental illustrates synthesis of cobalt complexeshaving 1°/3° ligand (L).

Referring to FIG. 39, cis-[Co(en)₂(NH₃)Cl]Cl₂ was prepared. A flamedried Schlenk flask was put under N₂ atmosphere and charged withtrans-[Co(en)₂Cl₂]Cl (0.6635 g, 2.232 mmol) which was suspended in dryMeOH (30 mL). The stirring suspension was warmed to 55° C. and anammonia solution (2.0 M in EtOH) (2.0 mL, 4.0 mmol) was added in a slowstream via syringe. The reaction mixture rapidly changes color fromgreen to red. For a few moments after the addition, the reaction mixturebecomes homogeneous. Immediately upon removing the reaction from the oilbath, a red precipitate begins to form. Returning the flask to the oilbath for 10 minutes did not dissolve the red precipitate and the mixturewas filtered while hot to yield a red-violet solid. The solid was washedwith MeOH and dried in air (1.362 g, 4.502 mmol).

Referring to FIG. 40, cis-[Co(en)₂(NH₃)NO₃]Cl₂ was prepared.cis-[Co(en)₂(NH₃)Cl]Cl₂ (1.361 g, 4.502 mmol) was dissolved in H₂O (3mL) and a solution of Hg(NO₃)₂ (2.55 g, 7.85 mmol) in concentrated HNO₃(4 mL) was added. The solution stirred at room temperature for 30 min.during which time the color changed from violet to orange-red as a heavywhite precipitate formed. The mixture was filtered though a plug ofcotton and the filtrate was diluted with EtOH (100 mL). After a fewminutes a sticky red precipitate formed. The flask was placed in anice-bath and after 30 minutes the EtOH was decanted. A mixture of 1:1EtOH/MeOH (100 mL) was added to the precipitate with vigorous stirring.After 5 minutes the alcohol solution was decanted and the red stickyresidue was dried by oil pump vacuum at room temperature overnight toyield a flaky red solid that was hygroscopic when exposed to air (1.1854g, 3.1016 mmol).

Referring to FIG. 41, cis-[Co(en)₂(NH₃){(NH₂(CH₂)2(NMe₂H+Cl—)}]Cl₂ wasprepared. cis-[Co(en)₂(NH₃)NO₃]Cl₂ (1.1854 g, 3.1016 mmol) was dissolvedin dry DMSO (5 mL) in a flame-dried Schlenk flask under N2 atmosphere.To the bright red solution was added N,N-dimethylethylenediamine (0.677mL, 6.20 mmol). The solution was stirred at room temperature for 6 hoursand a gradual color change from red to orange was observed and a smallamount of white precipitate developed. The reaction mixture was filteredand the filtrate was diluted with H₂O (20 mL) and loaded onto a Dowexcation exchange column. The orange band that sorbed to the top of thecolumn was washed with pure H₂O (100 mL) followed by 1 M HCl (100 mL).Then the band was eluted with 2 M HCl during which time a faint red bandwas separated from the intense orange band. The orange band wascollected and concentrated by rotary evaporation to yield an orangehygroscopic solid (0.8688 g, 2.034 mmol). 13C NMR (DMSO-d6, 125 MHz) δ56.6, 44.2, 44.0, 43.9, 43.3, 42.7, 42.5, 37.3.

Example 14 Werner Complexes in Enantioselective Hydrogen Bond MediatedCatalysis

Despite being inexpensive and readily available in enantiopure form,Werner complexes of the type [Co(en)₃]³⁺(en=ethylenediamine)((+)-Λ-1/(−)-Δ-1), and related species, have had no applications inenantioselective organic synthesis since their first preparation nearlya century ago.¹ This derives from their poor solubility in organicsolvents and the fact that the chelating amine ligands are non-labile,preventing metal based substrate activation. In light of recentadvancements in asymmetric hydrogen bond mediated catalysis by chiralalcohols, amines, and thioureas,² it was conceived that the abundantnitrogen-hydrogen bonds incorporated in the ethylenediamine units couldactivate Lewis basic substrates towards nucleophilic addition. Theenantiopure Δ-(−)-[Co(en)₃]³±cation became soluble in CH₂Cl₂ solvent bypairing with the large, non-coordinating aniontetrakis[(3,5-trifluoromethyl)phenyl]borate (BAr_(f) ⁻ ) and was used tocatalyze the Michael addition of dimethyl malonate totrans-β-nitrostyrene in the presence of triethylamine base in 99% yieldand 30% ee.

In efforts to improve enantioselectivity, related Werner-type complexeswith bulky, enantiopure(1S,2S)-diphenylethylenediamine (S,S-dpen)ligands were synthesized. Thus, a diastereomeric mixture of(+)-Λ-[Co(S,S-dpen)₃]Cl₃ and (−)-(Δ)-[Co(S,S-dpen)₃]Cl₃ was preparedaccording to an earlier synthesis.³ It was discovered that the anionexchange of these products with one molar equivalent of NaBAr_(f) led tothe CH₂Cl₂-soluble (+)-Λ-[Co(S,S-dpen)₃](BAr_(f))Cl₂ ((+)-Λ-2) and(−)-(Δ)-[Co(S,S-dpen)₃](BAr_(f))Cl₂ ((−)-Δ-2), which are easilyseparated by flash chromatography on silica gel.

The Werner complex (+)-Λ-2 demonstrated marked improvement in theenantioselectivity of the Michael addition by catalyzing the reaction in99% yield and 76% ee. Interestingly, the opposite catalyst diastereomer(−)-Δ-2, which bears the same absolute stereochemistry in the dpenligand but the opposite sense of chirality at the metal center, promotedthe same reaction with 99% yield and 56% ee of the opposite productenantiomer. This demonstrates that the enantioselectivity of the Michaeladdition is primarily under the control of the chirality at the metalcenter.

Some optimizations of the reaction conditions led to improvedenantioselectivities. It is generally observed that weaker bases promotebetter selectivity. For instance, the use of pyridine gave the Michaeladdition product in 80% ee. Surprisingly, the catalyst system performedwell even in polar solvents such as acetone, which promoted the Michaeladdition in 85% ee. This stands out as a unique feature, since mosthydrogen bond mediating catalysts are strongly inhibited by polarsolvents that are capable of competing with the substrate for hydrogenbonding sites. Additional examination reveals that enantioselectivity iseven further improved in the presence of water and an inorganic base,giving up to 90% ee.

Entry Catalyst Solvent Base % ee (% yield) 1 (−)-Δ-1 CH₂Cl₂ Et₃N 30 S(99) 2 (+)-Λ-2 CH₂Cl₂ Et₃N 76 R (99) 3 (−)-Δ-2 CH₂Cl₂ Et₃N 56 S (99) 4(+)-Λ-2 CH₂Cl₂ pyridine 80 R (50) 5 (+)-Λ-2 acetone Et₃N 85 R (99) 6(+)-Λ-2 CH₂Cl₂/H₂O Na₂CO₃ 90 R (99)

The Michael addition of diphenylphosphite to trans-β-nitrostyrene wascatalyzed by (+)-Λ-2 in 99% yield and 68% ee. The opposite catalystdiastereomer, (−)-Δ-2 promoted the same reaction in 99% yield to givethe opposite product enantiomer in 72% ee, again emphasizing that theabsolute product stereochemistry is determined by the chirality at themetal center.

Several derivative Werner complexes have been synthesized with modified,enantiopure S,S-dpen ligands including complexes with electron donating(3), electron withdrawing (4), and sterically bulky functional groups(5).

Werner-type complexes have here for the first time been successfullyemployed in enantioselective organic synthesis. The mode of activationby hydrogen bond mediation can be applied to a variety of substratesbearing hydrogen bond accepting functional groups. The structure of theS,S-dpen can be modified to allow for rapid fine tuning of theelectronic and steric properties of the catalyst to suit a particularreaction. These Werner-type complexes are inexpensive to prepare owinglargely to the low cost of cobalt and have been synthesized and resolvedinto pure diastereomers on a multi-gram scale. The catalysts are stablein the presence of air and moisture and are stored long term on thebench top. Lastly, recovery of the catalyst is possible by routinecolumn chromatography during the purification of the reaction mixture.

REFERENCES FOR EXAMPLE 15

-   1) Werner, A. Chem. Ber. 1912, 45, 121.-   2) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.-   3) Bosnich, B.; Harrowfield, J. Mac. B. J. Am. Chem. Soc. 1972, 94,    3425.

The examples herein are included to demonstrate particular embodimentsof the present invention. It should be appreciated by those of skill inthe art that the methods disclosed in the examples that follow merelyrepresent exemplary embodiments of the present invention. However, thoseof skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentsdescribed and still obtain a like or similar result without departingfrom the spirit and scope of the present invention.

Although the invention has been described with reference to specificembodiments, these descriptions are not meant to be construed in alimiting sense. Various modifications of the disclosed embodiments, aswell as alternative embodiments of the invention will become apparent topersons skilled in the art upon reference to the description of theinvention. It should be appreciated by those skilled in the art that theconception and the specific embodiment disclosed may be readily utilizedas a basis for modifying or designing other structures for carrying outthe same purposes of the present invention. It should also be realizedby those skilled in the art that such equivalent constructions do notdepart from the spirit and scope of the invention as set forth in theappended claims.

It is therefore, contemplated that the claims will cover any suchmodifications or embodiments that fall within the true scope of theinvention.

REFERENCES

-   1. Ghosh, A. K.; Leshchenko-Yashchuk, S.; Anderson, D. D.;    Baldridge, A.; Noetzel, M.; Miller, H. B.; Tie, Y. F.; Wang, Y.-F.;    Koh, Y.; Weber, I. T.; Mitsuya, H. J. Med. Chem. 2009, 52, 3902.-   2. Altman, J.; Ben-Ishai, D. Tetrahedron: Asymmetry 1993, 4, 91.-   3. Ganzmann, C. Doctorate Thesis, Universität Erlangen-Nürnberg,    2010.-   4. Chhabra, S. R.; Mahajan, A.; Chan, W. C. J. Org. Chem. 2002, 67,    4017.

What is claimed is:
 1. A compound, comprising a transition metal complexhaving the formula Φ-[M ((x,y)-L₁)_(3-b-c)((w,v)-L₂)_(b)((t,u)-L₃)_(c)]^(p+)An⁻ _(m)Z⁻ _(p-m), wherein Φ is Λ orΔ, wherein M is a transition metal, wherein p is an integercorresponding to the oxidation state of M, wherein each of x, y, w, v,t, and u independently comprises one of R and S, wherein each of L₁ andL₂ independently is a ligand comprising ethylene diamine, wherein L₃ isa ligand comprising an pendant Lewis base derivative of ethylenediamine, wherein c is from 1 to 3, wherein b is from 0 to 2, wherein An⁻comprises a lipophilic anion, wherein m is from 1 to 3, and wherein Z⁻comprises a second anion.
 2. The compound according to claim 1, whereinthe pendant Lewis base derivative of ethylene diamine comprisesEN(CH2)_(n)NR₁R₂, wherein EN represents ethylene diamine, and wherein nis from 2 to
 4. 3. The compound according to claim 1, wherein thetransition metal is selected from the group consisting of cobalt, iron,nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium,technetium, osmium, rhodium, iridium, platinum, and palladium.
 4. Thecompound according to claim 1, wherein the lipophilic anion is selectedfrom the group consisting of tetrakis[(3,5-trifluromethyl)phenyl]borate), tetrakis[pentafluorophenyl]borate,carboranes of the general formula CB₁₁H₁₂ ⁻, and its derivatives;TRISPHAT of the general formula P(O₂C₆Cl₄)³⁻, and1,1′-Binaphthyl-2,2′-diyl phosphates, and its derivatives.
 5. Acatalyst, comprising the compound of claim
 1. 6. The catalyst accordingto claim 5, wherein the catalyst has an enantioselectivity of at least60% for one or more of a carbon-carbon bond forming reaction, acarbon-heteroatom bond forming reaction, and a carbon-hydrogen bondforming reaction.
 7. The catalyst according to claim 5, wherein thecatalyst has a conversion rate of at least 95% for the one or more of acarbon-carbon bond forming reaction, a carbon-heteroatom bond formingreaction, and a carbon-hydrogen bond forming reaction.
 8. A compound,comprising a transition metal complex having the formula Φ-[M (x,y)-L₁(w,v)-L₂XY]^((p+a)+)An⁻ _(m)Z⁻ _(p-m), wherein Φ is Λ or Δ, wherein M isa transition metal, wherein p is an integer corresponding to theoxidation state of M, wherein each of x, y, w, and v independentlycomprises one of R and S, wherein each of L₁ and L₂ comprises achelating ligand comprising at least two nitrogens, wherein each of L₁and L₂ independently comprises a chelating ligand comprising at leasttwo metal coordinating atoms, wherein Y comprises a mono-coordinateddiamine ligand, wherein X comprises one out of a second mono-coordinateddiamine ligand and a nucleophilic ligand, wherein a is the total chargeof the mono-coordinated ligand(s), wherein An⁻ comprises a lipophilicanion, wherein m is from 1 to p, and wherein Z⁻ comprises a secondoptional anion.
 9. The compound according to claim 8, wherein each of L₁and L₂ independently comprises a chelating ligand comprising at leasttwo nitrogens.
 10. The compound according to claim 8, wherein thetransition metal is selected from the group consisting of cobalt, iron,nickel, chromium, manganese, molybdenum, tungsten, rhenium, ruthenium,technetium, osmium, rhodium, iridium, platinum, and palladium.
 11. Thecompound according to claim 8, wherein the lipophilic anion is selectedfrom the group consisting of tetrakis[(3,5-trifluromethyl)phenyl]borate), tetrakis[pentafluorophenyl]borate,carboranes of the general formula CB₁₁H₁₂ ⁻, and its derivatives;TRISPHAT of the general formula P(O₂C₆Cl₄)³⁻, and1,1′-Binaphthyl-2,2′-diyl phosphates, and its derivatives.
 12. Acatalyst, comprising the compound of claim
 8. 13. The catalyst accordingto claim 12, wherein the catalyst has an enantioselectivity of at least60% for one or more of a carbon-carbon bond forming reaction, acarbon-heteroatom bond forming reaction, and a carbon-hydrogen bondforming reaction.
 14. The catalyst according to claim 12, wherein thecatalyst has a conversion rate of at least 95% for the one or more of acarbon-carbon bond forming reaction, a carbon-heteroatom bond formingreaction, and a carbon-hydrogen bond forming reaction.